(en)This invention provides novel targeted antimicrobial compositions. In various embodiments chimeric moieties are provided comprising an antimicrobial peptide attached to a peptide targeting moiety that binds a bacterial strain or species.

1.ApplicationNumber: US-201715433926-A
1.PublishNumber: US-2017266306-A1
2.Date Publish: 20170921
3.Inventor: ECKERT RANDAL H.
KAPLAN CHRIS
HE JIAN
YARBROUGH DANIEL K.
ANDERSON MAXWELL
SIM JEE-HYUN

4.Inventor Harmonized: ECKERT RANDAL H(US)
KAPLAN CHRIS(US)
HE JIAN(CN)
YARBROUGH DANIEL K(US)
ANDERSON MAXWELL(US)
SIM JEE-HYUN(US)

5.Country: US
6.Claims:
(en)This invention provides novel targeted antimicrobial compositions. In various embodiments chimeric moieties are provided comprising an antimicrobial peptide attached to a peptide targeting moiety that binds a bacterial strain or species.

7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Divisional of U.S. Ser. No. 14/255,858, filed Apr. 17, 2014, which is a Divisional of U.S. Ser. No. 12/683,160, filed Jan. 6, 2010 issued as U.S. Pat. No. 8,754,039 on Jun. 17, 2014, which claims benefit of and priority to U.S. Ser. No. 61/142,830, filed Jan. 6, 2009, U.S. Ser. No. 61/151,445, filed Feb. 10, 2009, U.S. Ser. No. 61/243,905, filed Sep. 18, 2009, and U.S. Ser. No. 61/243,930, filed Sep. 18, 2009, all of which are incorporated herein by reference in their entirety for all purposes.


STATEMENT OF GOVERNMENTAL SUPPORT
[Not Applicable]
FIELD OF THE INVENTION
The present invention relates to novel targeting peptides, novel antimicrobial peptides, chimeric moieties comprising novel targeting and/or novel antimicrobial peptides and uses thereof.
BACKGROUND OF THE INVENTION
Antibiotic research at the industrial level was originally focused on the identification of refined variants of already existing drugs. This resulted example, in the development of antibiotics such as newer penicillins, cephalosporins, macrolides, and fluoroquinolones.
However, resistance to old and newer antibiotics among bacterial pathogens is evolving rapidly, as exemplified by extended beta-lactamase (ESBL) and quinolone resistant gram-negatives, multi-resistant gonococci, methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE), penicillin non-susceptible pneumococci (PNSP) and macrolide resistant pneumococci and streptococci (see, e.g., Panlilo et al. (1992) Infect Control Hosp Epidemio., 13: 582-586; Morris et al. (1995) Ann Intern Me., d 123: 250-259, and the like). An overuse, or improper use, of antibiotics is believed to be of great importance for triggering and spread of drug resistant bacteria. Microbes have, in many cases, adapted and are resistant to antibiotics due to constant exposure and improper use of the drugs.
Drug resistant pathogens represent a major economic burden for health-care systems. For example, postoperative and other nosocomial infections will prolong the need for hospital care and increase antibiotic drug expenses. It is estimated that the annual cost of treating drug resistant infections in the United States is approximately $5 billion.
SUMMARY OF THE INVENTION
In certain embodiments, novel targeting moieties (e.g., peptides) that specifically/preferentially bind to microorganisms (e.g., certain bacteria, yeasts, fungi, molds, viruses, algae, protozoa, and the like) are provided. The targeting moieties can be attached to effectors (e.g., detectable labels, drugs, antimicrobial peptides, etc.) to form chimeric constructs for specifically/preferentially delivering the effector to and/or into the target organism. In certain embodiments novel antimicrobial peptides that can be used to inhibit (e.g., kill and/or inhibit growth and/or proliferation) of certain microorganisms (e.g., certain bacteria, yeasts, fungi, molds, viruses, algae, protozoa, and the like) are provided.
Accordingly, in certain embodiments, a chimeric construct (chimeric moiety) is provided comprising: an effector attached to a peptide targeting moiety comprising an amino acid sequence found in Table 3 and/or Table 12; and/or an antimicrobial peptide comprising an amino acid sequence found in Table 4 and/or Table 5 attached to a targeting moiety. In certain embodiments the targeting moiety is a peptide comprising an amino acid sequence of a peptide found one or more of Table 3 and Table 12. In certain embodiments the targeting moiety is a peptide comprising two or more amino acid sequences of a peptide found one or more of Table 3 and Table 12. In certain embodiments the targeting moiety is a peptide whose amino acid sequence consists of the amino acid sequence of a peptide found in Table 3.
In various embodiments the effector comprises a moiety selected from the group consisting of an antimicrobial peptide, an antibiotic, a ligand, a lipid or liposome, a agent that physically disrupts the extracellular matrix within a community of microorganisms, and a polymeric particle. In certain embodiments the effector comprises an antimicrobial peptide comprising an amino acid sequence found in one or more of Tables 4, 5, 14, and Table 15. In certain embodiments the effector comprises an antimicrobial peptide comprising an amino acid sequence found in one or more of Tables 4, and 5. In certain embodiments the effector comprises an antimicrobial peptide comprising an amino acid sequence characterized by a motif selected from the group consisting of KIF, FIK, KIH, HIK, and KIV (e.g., as identified in Table 7). In certain embodiments the construct comprises a targeting peptide comprising an amino acid sequence found in Table 3 attached to an antimicrobial peptide comprising an amino acid sequence found in Table 4 and/or Table 5. In certain embodiments the construct comprises an antimicrobial peptide comprising an amino acid sequence found in Table 4 attached to a targeting moiety comprising an amino acid sequence found in Table 3 and/or Table 10, and/or Table 12. In certain embodiments the construct comprises a targeting peptide comprising an amino acid sequence found in Table 3 attached to an antimicrobial peptide comprising an amino acid sequence found in Table 4.
In various embodiments the targeting moiety is chemically conjugated to the effector (directly or via a linker). In certain embodiments the liker comprises a polyethylene glycol (PEG). In certain embodiments the targeting moiety is chemically conjugated to the effector via a non-peptide linker found in Table 16. In certain embodiments the targeting moiety is linked to the effector via a peptide linkage. In certain embodiments the effector comprises an antimicrobial peptide and the construct is a fusion protein. In certain embodiments the targeting moiety is attached to the effector by a peptide linker comprising or consisting of an amino acid sequence found in Table 16. In certain embodiments any of the constructs and/or peptides described herein bears one or more protecting groups. In certain embodiments the one or more protecting groups are independently selected from the group consisting of acetyl, amide, 3 to 20 carbon alkyl groups, fmoc, tboc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, xanthyl (Xan), trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO), benzyl (Bzl), benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl—Z), 2-bromobenzyloxycarbonyl (2-Br—Z), benzyloxymethyl (Bom), t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), and trifluoroacetyl (TFA). In certain embodiments the peptide and/or construct comprises a protecting group at a carboxyl and/or amino terminus. In certain embodiments the carboxyl terminus is amidated and/or the amino terminus is acetylated. In various embodiments the chimeric construct and/or peptide is functionalized with a polymer (e.g., comprises polyethylene glycol, cellulose, modified cellulose, dextrin, etc.) to increase serum halflife.
In certain embodiments pharmaceutical compositions are provided. In various embodiments the pharmaceutical compositions comprise a chimeric construct as described herein (e.g., a chimeric construct according to any of claims 1 - 26 ) and/or an antimicrobial peptide as described herein, in a pharmaceutically acceptable carrier. In certain embodiments the composition is formulated as a unit dosage formulation. In certain embodiments the composition is formulated for administration by a modality selected from the group consisting of intraperitoneal administration, topical administration, oral administration, inhalation administration, transdermal administration, subdermal depot administration, systemic IV application, ocular administration, and rectal administration.
In certain embodiments isolated antimicrobial peptides are provided. In various embodiments the peptides comprise one or more sequences selected from the amino acid sequences listed in Table 4 and/or Table 5 (and/or the retro, inverso, retroinverso, or beta forms). In various embodiments the antimicrobial peptide bears one or more protecting groups e.g., as described herein.
In certain embodiments a composition effective to kill or to inhibit the growth and/or of a microorganism and/or the formation and/or maintenance of a biofilm is provided. The composition typically comprises one or more isolated antimicrobial peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the amino acid sequences listed in Table 4 and/or Table 5 (and/or their retro, inverso, or retroinverso forms). In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of a yeast or fungus, and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified (e.g., in those tables) as effective to effective to kill or inhibit the growth and/or proliferation of a yeast or fungus. In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of Aspergillus niger and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of Aspergillus niger . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of C. albicans and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of C. albicans . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of T. rubrum and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of T. rubrum . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of a bacterium, and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of a bacterium. In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of a gram positive bacterium, and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of a gram positive bacterium. In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of A. naeslundii , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of A. naeslundii . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of B. subtilis , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of B. subtilis . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of C. difficile , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of C. difficile . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of C. jeikeium , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of C. jeikeium . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of E. faecalis , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of E. faecalis . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of M. luteus , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of M. luteus . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of MRSA, and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of MRSA. In certain embodiments composition is effective to kill or inhibit the growth and/or proliferation of S. epidermidis , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of S. epidermidis . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of S. mutans , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of S. mutans . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of S. pneumoniae , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of S. pneumoniae . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of a gram negative bacterium, and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of a gram negative bacterium. In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of A. baumannii , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of A. baumannii . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of C. jejuni , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of C. jejuni . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of E. coli , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of E. coli . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of F. nucleatum , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of F. nucleatum . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of E. coli , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of M. xanthus . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of P. aeruginosa , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of P. aeruginosa . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of P. gingivalis , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of P. gingivalis . In certain embodiments the composition is effective to kill or inhibit the growth and/or proliferation of P. mirabilis , and the composition comprises one or more peptides, the amino acid sequences of the peptides comprising one or more sequences selected from the group of amino acid sequences listed in Table 4 and/or Table 5 identified as effective to effective to kill or inhibit the growth and/or proliferation of P. mirabilis.
In various embodiments one or more of the peptides comprising the composition comprise all “L” amino acids or all “D” amino acids, or a mixture of “L” and “D” amino acids. In various embodiments one or more of the peptides comprising the composition are β peptides. In various embodiments one or more of the peptides comprising the composition comprise one or more protecting groups (e.g. protected carboxyl and/or amino termini). In various embodiments one or more of the peptides comprising the composition comprise an amide on the carboxyl terminus and/or an acetyl on the amino terminus. In various embodiments the peptides comprising the composition are in a pharmaceutically acceptable carrier. In certain embodiments the carrier is suitable for administration via a route selected from the group consisting of topical administration, aerosol administration, administration via inhalation, oral administration, and/or rectal administration.
In various embodiments methods are provided for killing and/or inhibiting the growth and/or proliferation of a microorganism and or for disrupting and/or inhibiting the growth and/or maintenance of a biofilm, the method comprising contacting the microorganism (or a biofilm comprising the microorganism) with a chimeric construct as described herein (e.g., see description above, and/or a chimeric construct according to any one of claims 1 - 29 ), or with an antimicrobial peptide as described herein, and/or with a composition as described herein (e.g., a composition according to any one of claims 30 - 65 ). In certain embodiments the microorganism is a yeast or fungus and the chimeric construct or composition is a chimeric construct comprising an effector identified as killing a yeast or fungus, or a composition comprising an antimicrobial peptide described herein as killing a yeast or fungus. In certain embodiments the microorganism is a bacterium (e.g., gram negative and/or gram positive bacterium) and the chimeric construct or composition is a chimeric construct comprising an effector identified as killing a bacterium (e.g., gram negative and/or gram positive bacterium), or a composition comprising an antimicrobial peptide described herein as killing a gram negative and/or gram positive bacterium. In certain embodiments the effector is an antimicrobial peptide. In certain embodiments he microorganism is S. mutans , and the chimeric construct or composition is applied to the oral cavity of an animal or human, e.g., to reduces the incidence or severity of dental caries and/or periodontal disease). In certain embodiments the chimeric construct or composition preferentially targets Corynebacterium spp. and the chimeric construct or composition is applied to the skin surface of an animal or human (e.g., to reduce body odor).
Methods are also provided for disinfecting a surface. The methods typically involve contacting the surface with one or more chimeric constructs described herein (e.g. a construct according to any one of claims 1 - 29 ), or a composition as described herein (e.g., a composition according to any one of claims 30 - 65 ). In certain embodiments, the surface comprises a surface of a prosthesis or medical implant. In certain embodiments the surface comprises a surface of a medical device. In certain embodiments the surface comprises a surface of a plant or foodstuff. In certain embodiments the chimeric construct and/or the antimicrobial peptide(s) are combined with a second disinfectant selected from the group consisting of other antimicrobial agent is a disinfectant selected from the group consisting of acetic acid, phosphoric acid, citric acid, lactic, formic, propionic acid, hydrochloric acid, sulfuric acid, nitric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, ethyl alcohol, isopropyl alcohol, phenol, formaldehyde, glutaraldehyde, hypochlorites, chlorine dioxide, sodium dichloroisocyanurate, chloramine-T, iodine, povidone-iodine, chlorhexidine, hydrogen peroxide, peracetic acid, and benzalkonium chloride.
In various embodiments the use of a chimeric construct described herein and/or an antimicrobial composition as described herein (e.g., a chimeric construct according to any one of claims 1 - 29 , or a composition according to any one of claims 30 - 65 ) in the manufacture of a medicament for killing and/or inhibiting the growth and/or proliferation of a microorganism and/or inhibiting the growth and/or maintenance of a biofilm comprising the microorganism is provided. In certain embodiments the microorganism is a yeast or fungus and the chimeric construct or composition is a chimeric construct comprising an effector identified as killing a yeast or fungus, or a composition comprising an antimicrobial peptide described herein as killing a yeast or fungus. In certain embodiments the microorganism is a bacterium (e.g., gram negative and/or gram positive bacterium) and the chimeric construct or composition is a chimeric construct comprising an effector identified as killing a bacterium (e.g., gram negative and/or gram positive bacterium), or a composition comprising an antimicrobial peptide described herein as killing a gram negative and/or gram positive bacterium. In certain embodiments the effector is an antimicrobial peptide.
In various embodiments methods are also provided for of detecting a bacterium and/or a bacterial film (e.g., a biofilm comprising the bacteria). The methods typically involve contacting the bacterium or bacterial film with a composition comprising a detectable label attached to a targeting peptide comprising one or more amino acid sequences found Table 3 and/or Table 12; and detecting the detectable label where the quantity and/or location of the detectable label is an indicator of the presence of the bacterium and/or bacterial film. In certain embodiments the targeting peptide comprises or consists of an amino acid sequence of a peptide found in Table 3 (and/or the retro, inverso, retroinverso form of the sequence). In certain embodiments the detectable label is a label selected from the group consisting of a radioactive label, a radio-opaque label, a fluorescent dye, a fluorescent protein, an enzymatic label, a colorimetric label, and a quantum dot.
Certain compositions are also provided comprising a photosensitizing or photoactivatable agent attached to a targeting peptide (e.g., a peptide comprising an amino acid sequence of a peptide found in Table 3 and/or Table 12). In certain embodiments the targeting peptide comprises or consists of an amino acid sequence of a peptide found in Table 3. In certain embodiments the photosensitizing agent is an agent selected from the group consisting of a porphyrinic macrocycle, a porphyrin, a chlorine, a crown ether, an acridine, an azine, a phthalocyanine, a cyanine, a psoralen, a cucumin, and a perylenequinonoid. In certain embodiments the photosensitizing agent comprises one or more agents agent shown in any of FIGS. 1-12 . In certain embodiments the photosensitizing agent is attached to the targeting peptide by a non-peptide linker (e.g., a polyethylene glycol (PEG)). In certain embodiments the photosensitizing agent is attached to the targeting peptide by a non-peptide linker found in Table 16.
In various embodiments methods are provided for killing and/or for inhibiting the growth and/or proliferation of a microorganism or a biofilm comprising a microorganism, where the methods involve contacting the microorganism or biofilm with a composition comprising a photosensitizing or photoactivatable agent attached to a targeting peptide (e.g., a peptide comprising an amino acid sequence of a peptide found in Table 3 and/or Table 12). In certain embodiments the targeting peptide comprises or consists of an amino acid sequence of a peptide found in Table 3. In certain embodiments the photosensitizing agent is an agent selected from the group consisting of a porphyrinic macrocycle, a porphyrin, a chlorine, a crown ether, an acridine, an azine, a phthalocyanine, a cyanine, a psoralen, a cucumin, and a perylenequinonoid. In certain embodiments the photosensitizing agent comprises one or more agents agent shown in any of FIGS. 1-12 . In certain embodiments the photosensitizing agent is attached to the targeting peptide by a non-peptide linker (e.g., a polyethylene glycol (PEG)). In certain embodiments the photosensitizing agent is attached to the targeting peptide by a non-peptide linker found in Table 16. In certain embodiments the method further comprises exposing the microorganism or biofilm to a light source. In certain embodiments the microorganism is a microorganism selected from the group consisting of a bacterium (e.g., a gram positive and/or a gram negative bacterium), a yeast, a fungus, a protozoan, and a virus. In certain embodiments the biofilm comprises a bacterial film. In certain embodiments the biofilm is a biofilm on an implanted or implantable medical device. In certain embodiments the microorganism or biofilm is an organism or biofilm in an oral cavity.
In various embodiments certain formulations are provided. Typical formulations include, but are not limited to a targeting peptide, an antimicrobial peptide, and/or a STAMP; and a salt at a concentration comparable to that found in phosphate buffered saline (PBS) ranging from about 0.5×PBS to about 2.5×PBS. In certain embodiments the formulation comprises a targeting peptide found in Tables 3 or 10. In certain embodiments the formulation comprises an anti- S. mutans peptide targeting peptide (e.g., as identified in Tables 3 or 12). In certain embodiments the anti- S. mutans targeting peptide has the amino acid sequence TFFRLFNRSFTQALGK (SEQ ID NO:1). In certain embodiments the anti- S. mutans targeting peptide is attached to an antimicrobial peptide. In certain embodiments the antimicrobial peptide is a peptide found in Tables 4, 5, or 14. In certain embodiments the antimicrobial peptide has the amino acid sequence KNLRIIRKGIHIIKKY (SEQ ID NO:3080). In certain embodiments the formulation comprises the amino acid sequence of the C16G2 STAMP (TFFRLFNRSFTQALGKGGGKNLRIIRKGIHIIKKY, (SEQ ID NO:2). In various embodiments the targeting peptide, antimicrobial peptide, and/or a STAMP bears one or more protecting groups. In certain embodiments the protecting group(s) are independently selected from the group consisting of acetyl, amide, 3 to 20 carbon alkyl groups, Fmoc, Tboc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO), Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl—Z), 2-bromobenzyloxycarbonyl (2-Br—Z), Benzyloxymethyl (Born), t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), and Trifluoroacetyl (TFA). In certain embodiments the targeting peptide, antimicrobial peptide, and/or a STAMP is amidated at the carboxyl terminus and/or bears an acetyl group at the amino terminus. In certain embodiments the pH of the formulation ranges from about pH 5.0 to about pH 8.5. In certain embodiments the pH is about pH 7.4. In various embodiments the salt is at a concentration comparable to that found in 1×PBS. In certain embodiments the formulation comprises PBS. In certain embodiments the formulation of further comprising ethanol, and/or glycerin, and/or polyethylene glycol, and/or fluoride.
Definitions
The term “peptide” as used herein refers to a polymer of amino acid residues typically ranging in length from 2 to about 50 or about 60 residues. In certain embodiments the peptide ranges in length from about 2, 3, 4, 5, 7, 9, 10, or 11 residues to about 60, 50, 45, 40, 45, 30, 25, 20, or 15 residues. In certain embodiments the peptide ranges in length from about 8, 9, 10, 11, or 12 residues to about 15, 20 or 25 residues. In certain embodiments the amino acid residues comprising the peptide are “L-form” amino acid residues, however, it is recognized that in various embodiments, “D” amino acids can be incorporated into the peptide. Peptides also include amino acid polymers in which one or more amino acid residues is an artificial chemical analogue of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. In addition, the term applies to amino acids joined by a peptide linkage or by other, “modified linkages” (e.g., where the peptide bond is replaced by an α-ester, a β-ester, a thioamide, phosphonamide, carbonate, hydroxylate, and the like (see, e.g., Spatola, (1983) Chem. Biochem. Amino Acids and Proteins 7: 267-357), where the amide is replaced with a saturated amine (see, e.g., Skiles et al., U.S. Pat. No. 4,496,542, which is incorporated herein by reference, and Kaltenbronn et al., (1990) Pp. 969-970 in Proc. 11th American Peptide Symposium, ESCOM Science Publishers, The Netherlands, and the like)).
The term “residue″” as used herein refers to natural, synthetic, or modified amino acids. Various amino acid analogues include, but are not limited to 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine (beta-aminopropionic acid), 2-aminobutyric acid, 4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4 diaminobutyric acid, desmosine, 2,2′-diaminopimelic acid, 2,3-diaminopropionic acid, n-ethylglycine, n-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, n-methylglycine, sarcosine, n-methylisoleucine, 6-n-methyllysine, n-methylvaline, norvaline, norleucine, ornithine, and the like. These modified amino acids are illustrative and not intended to be limiting.
“β-peptides” comprise of “β amino acids”, which have their amino group bonded to the β carbon rather than the α-carbon as in the 20 standard biological amino acids. The only commonly naturally occurring β amino acid is β-alanine.
Peptoids, or N-substituted glycines, are a specific subclass of peptidomimetics. They are closely related to their natural peptide counterparts, but differ chemically in that their side chains are appended to nitrogen atoms along the molecule's backbone, rather than to the α-carbons (as they are in natural amino acids).
The terms “conventional” and “natural” as applied to peptides herein refer to peptides, constructed only from the naturally-occurring amino acids: Ala, Cys, Asp, Glu, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr. A compound of the invention “corresponds” to a natural peptide if it elicits a biological activity (e.g., antimicrobial activity) related to the biological activity and/or specificity of the naturally occurring peptide. The elicited activity may be the same as, greater than or less than that of the natural peptide. In general, such a peptoid will have an essentially corresponding monomer sequence, where a natural amino acid is replaced by an N-substituted glycine derivative, if the N-substituted glycine derivative resembles the original amino acid in hydrophilicity, hydrophobicity, polarity, etc. The following are illustrative, but non-limiting N-substituted glycine replacements: N-(1-methylprop-1-yl)glycine substituted for isoleucine (Ile), N-(prop-2-yl)glycine for valine (Val), N-benzylglycine for phenylanlaine (Phe), N-(2-hydroxyethyl)glycine for serine (Ser), and the like. In certain embodiments substitutions need not be “exact”. Thus for example, in certain embodiments N-(2-hydroxyethyl)glycine may substitute for Ser, Thr, Cys, and/or Met; N-(2-methylprop-1-yl)glycine may substitute for Val, Leu, and/or Ile. In certain embodiments N-(2-hydroxyethyl)glycine can be used to substitute for Thr and Ser, despite the structural differences: the side chain in N-(2-hydroxyethyl)glycine is one methylene group longer than that of Ser, and differs from Thr in the site of hydroxy-substitution. In general, one may use an N-hydroxyalkyl-substituted glycine to substitute for any polar amino acid, an N-benzyl- or N-aralkyl-substituted glycine to replace any aromatic amino acid (e.g., Phe, Trp, etc.), an N-alkyl-substituted glycine such as N-butylglycine to replace any nonpolar amino acid (e.g., Leu, Val, Ile, etc.), and an N-(aminoalkyl)glycine derivative to replace any basic polar amino acid (e.g., Lys and Arg).
Where an amino acid sequence is provided herein, L-, D-, or beta amino acid versions of the sequence are also contemplated as well as retro, inversion, and retro-inversion isoforms. In addition, conservative substitutions (e.g., in the binding peptide, and/or antimicrobial peptide, and/or linker peptide) are contemplated. Non-protein backbones, such as PEG, alkane, ethylene bridged, ester backbones, and other backbones are also contemplated. Also fragments ranging in length from about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids up to the full length minus one amino acid of the peptide are contemplated where the fragment retains at least 50%, preferably at least 60% 70% or 80%, more preferably at least 90%, 95%, 98%, 99%, or at least 100% of the activity (e.g., binding specificity and/or avidity, antimicrobial activity, etc.) of the full length peptide are contemplated.
A “compound antimicrobial peptide” or “compound AMP” refers to a construct comprising two or more AMPs joined together. The AMPs can be joined directly or through a linker. They can be chemically conjugated or, where joined directly together or through a peptide linker can comprise a fusion protein.
In certain embodiments, conservative substitutions of the amino acids comprising any of the sequences described herein are contemplated. In various embodiments one, two, three, four, or five different residues are substituted. The term “conservative substitution” is used to reflect amino acid substitutions that do not substantially alter the activity (e.g., antimicrobial activity and/or specificity) of the molecule. Typically conservative amino acid substitutions involve substitution one amino acid for another amino acid with similar chemical properties (e.g. charge or hydrophobicity). Certain conservative substitutions include “analog substitutions” where a standard amino acid is replaced by a non-standard (e.g., rare, synthetic, etc) amino acid differing minimally from the parental residue. Amino acid analogs are considered to be derived synthetically from the standard amino acids without sufficient change to the structure of the parent, are isomers, or are metabolite precursors. Examples of such “analog substitutions” include, but are not limited to, 1) Lys-Orn, 2) Leu-Norleucine, 3) Lys-Lys[TFA], 4) Phe-Phe[Gly], and 5) δ-amino butylglycine-ξ-amino hexylglycine, where Phe[gly] refers to phenylglycine (a Phe derivative with a H rather than CH 3 component in the R group), and Lys[TFA] refers to a Lys where a negatively charged ion (e.g., TFA) is attached to the amine R group. Other conservative substitutions include “functional substitutions” where the general chemistries of the two residues are similar, and can be sufficient to mimic or partially recover the function of the native peptide. Strong functional substitutions include, but are not limited to 1) Gly/Ala, 2) Arg/Lys, 3) Ser/Tyr/Thr, 4) Leu/Ile/Val, 5) Asp/Glu, 6) Gln/Asn, and 7) Phe/Trp/Tyr, while other functional substitutions include, but are not limited to 8) Gly/Ala/Pro, 9) Tyr/His, 10) Arg/Lys/His, 11) Ser/Thr/Cys, 12) Leu/Ile/Val/Met, and 13) Met/Lys (special case under hydrophobic conditions). Various “broad conservative substations” include substitutions where amino acids replace other amino acids from the same biochemical or biophysical grouping. This is similarity at a basic level and stems from efforts to classify the original 20 natural amino acids. Such substitutions include 1) nonpolar side chains: Gly/Ala/Val/Leu/Ile/Met/Pro/Phe/Trp, and/or 2) uncharged polar side chains Ser/Thr/Asn/Gln/Tyr/Cys. In certain embodiments broad-level substitutions can also occur as paired substitutions. For example, Any hydrophilic neutral pair [Ser, Thr, Gln, Asn, Tyr, Cys]+[Ser, Thr, Gln, Asn, Tyr, Cys] can may be replaced by a charge-neutral charged pair [Arg, Lys, His]+[Asp, Glu]. The following six groups each contain amino acids that, in certain embodiments, are typical conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K), Histidine (H); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). Where amino acid sequences are disclosed herein, amino acid sequences comprising, one or more of the above-identified conservative substitutions are also contemplated.
In certain embodiments, targeting peptides, antimicrobial peptides, and/or STAMPs compromising at least 80%, preferably at least 85% or 90%, and more preferably at least 95% or 98% sequence identity with any of the sequences described herein are also contemplated. The terms “identical” or percent “identity,” refer to two or more sequences that are the same or have a specified percentage of amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection. With respect to the peptides of this invention sequence identity is determined over the full length of the peptide. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman (1981) Adv. Appl. Math. 2: 482, by the homology alignment algorithm of Needleman & Wunsch (1970) J Mol. Biol. 48: 443, by the search for similarity method of Pearson & Lipman (1988) Proc. Natl. Acad. Sci., USA, 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection.
The term “specificity” when used with respect to the antimicrobial activity of a peptide indicates that the peptide preferentially inhibits growth and/or proliferation and/or kills a particular microbial species as compared to other related and/or unrelated microbes. In certain embodiments the preferential inhibition or killing is at least 10% greater (e.g., LD 50 is 10% lower), preferably at least 20%, 30%, 40%, or 50%, more preferably at least 2-fold, at least 5-fold, or at least 10-fold greater for the target species.
“Treating” or “treatment” of a condition as used herein may refer to preventing the condition, slowing the onset or rate of development of the condition, reducing the risk of developing the condition, preventing or delaying the development of symptoms associated with the condition, reducing or ending symptoms associated with the condition, generating a complete or partial regression of the condition, or some combination thereof.
The term “consisting essentially of” when used with respect to an antimicrobial peptide (AMP) or AMP motif as described herein, indicates that the peptide or peptides encompassed by the library or variants, analogues, or derivatives thereof possess substantially the same or greater antimicrobial activity and/or specificity as the referenced peptide. In certain embodiments substantially the same or greater antimicrobial activity indicates at least 80%, preferably at least 90%, and more preferably at least 95% of the anti microbial activity of the referenced peptide(s) against a particular bacterial species (e.g., S. mutans ).
The term “porphyrinic macrocycle” refers to a porphyrin or porphyrin derivative. Such derivatives include porphyrins with extra rings ortho-fused, or orthoperifused, to the porphyrin nucleus, porphyrins having a replacement of one or more carbon atoms of the porphyrin ring by an atom of another element (skeletal replacement), derivatives having a replacement of a nitrogen atom of the porphyrin ring by an atom of another element (skeletal replacement of nitrogen), derivatives having substituents other than hydrogen located at the peripheral (meso-, .beta.-) or core atoms of the porphyrin, derivatives with saturation of one or more bonds of the porphyrin (hydroporphyrins, e.g., chlorins, bacteriochlorins, isobacteriochlorins, decahydroporphyrins, corphins, pyrrocorphins, etc.), derivatives obtained by coordination of one or more metals to one or more porphyrin atoms (metalloporphyrins), derivatives having one or more atoms, including pyrrolic and pyrromethenyl units, inserted in the porphyrin ring (expanded porphyrins), derivatives having one or more groups removed from the porphyrin ring (contracted porphyrins, e.g., corrin, corrole) and combinations of the foregoing derivatives (e.g. phthalocyanines, porphyrazines, naphthalocyanines, subphthalocyanines, and porphyrin isomers). Certain porphyrinic macrocycles comprise at least one 5-membered ring.
As used herein, an “antibody” refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
A typical immunoglobulin (antibody) structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (V L ) and variable heavy chain (V H ) refer to these light and heavy chains respectively.
Antibodies exist as intact immunoglobulins or as a number of well characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′ 2 , a dimer of Fab which itself is a light chain joined to V H -C H 1 by a disulfide bond. The F(ab)′ 2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab′) 2 dimer into an Fab′ monomer. The Fab′ monomer is essentially an Fab with part of the hinge region (see, Fundamental Immunology , W.E. Paul, ed., Raven Press, N.Y. (1993), for a more detailed description of other antibody fragments). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such Fab′ fragments may be synthesized de novo either chemically or by utilizing recombinant DNA methodology. Thus, the term antibody, as used herein also includes antibody fragments either produced by the modification of whole antibodies or synthesized de novo using recombinant DNA methodologies, including, but are not limited to, Fab′ 2 , IgG, IgM, IgA, scFv, dAb, nanobodies, unibodies, and diabodies.
In certain embodiments antibodies and fragments of the present invention can be bispecific. Bispecific antibodies or fragments can be of several configurations. For example, bispecific antibodies may resemble single antibodies (or antibody fragments) but have two different antigen binding sites (variable regions). In various embodiments bispecific antibodies can be produced by chemical techniques (Kranz et al. (1981) Proc. Natl. Acad. Sci., USA, 78: 5807), by “polydoma” techniques (see, e.g., U.S. Pat. No. 4,474,893), or by recombinant DNA techniques. In certain embodiments bispecific antibodies of the present invention can have binding specificities for at least two different epitopes, at least one of which is an epitope of a microbial organism. The microbial binding antibodies and fragments can also be heteroantibodies. Heteroantibodies are two or more antibodies, or antibody binding fragments (e.g., Fab) linked together, each antibody or fragment having a different specificity.
The term “STAMP” refers to Specifically Targeted Anti-Microbial Peptides. In various embodiments, a STAMP comprises one or more peptide targeting moieties attached to one or more antimicrobial moieties (e.g.., antimicrobial peptides (AMPs)). An MH-STAMP is a STAMP bearing two or more targeting domains (i.e., a multi-headed STAMP).
The terms “isolated” “purified” or “biologically pure” refer to material which is substantially or essentially free from components that normally accompany it as found in its native state. In the case of a peptide, an isolated (naturally occurring) peptide is typically substantially free of components with which it is associated in the cell, tissue, or organism. The term isolated also indicates that the peptide is not present in a phage display, yeast display, or other peptide library.
In various embodiments the amino acid abbreviations shown in Table 1 are used herein.





TABLE 1



Amino acid abbreviations.






Abbreviation








Name
3 Letter
1 Letter





Alanine
Ala
A


βAlanine
βAla


(NH 2 —CH 2 —CH 2 —COOH)


Arginine
Arg
R


Asparagine
Asn
N


Aspartic Acid
Asp
D


Cysteine
Cys
C


Glutamic Acid
Glu
E


Glutamine
Gln
Q


Glycine
Gly
G


Histidine
His
H


Homoserine
Hse
—


Isoleucine
Ile
I


Leucine
Leu
L


Lysine
Lys
K


Methionine
Met
M


Methionine sulfoxide
Met (O)
—


Methionine methylsulfonium
Met (S-Me)
—


Norleucine
Nle
—


Phenylalanine
Phe
F


Proline
Pro
P


Serine
Ser
S


Threonine
Thr
T


Tryptophan
Trp
W


Tyrosine
Tyr
Y


Valine
Val
V


episilon-aminocaproic acid
Ahx
J


(NH 2 —(CH 2 ) 5 —COOH)


4-aminobutanoic acid
gAbu


(NH 2 —(CH 2 ) 3 —COOH)


tetrahydroisoquinoline-3-

O


carboxylic acid


Lys(N(epsilon)-trifluoroacetyl)

K[TFA]


α-aminoisobutyric acid
Aib
B






























































BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows some illustrative porphyrins (compounds 92-99) suitable for use as targeting moieties and/or antimicrobial effectors.
FIG. 2 shows some illustrative porphyrins (compounds 100-118) suitable for use as targeting moieties and/or antimicrobial effectors.
FIG. 3 shows some illustrative porphyrins (in particular phthalocyanines) (compounds 119-128) suitable for use as targeting moieties and/or antimicrobial effectors.
FIG. 4 illustrates the structures of two phthalocyanines, Monoastral Fast Blue B and Monoastral Fast Blue G suitable for use as targeting moieties and/or antimicrobial effectors.
FIG. 5 illustrates certain azine photosensitizers suitable for use as targeting moieties and/or antimicrobial effectors in the compositions and methods described herein.
FIG. 6 shows illustrative cyanine suitable for use as targeting moieties and/or antimicrobial effectors in the compositions and methods described herein.
FIG. 7 shows illustrative psoralen (angelicin) photosensitizers suitable for use as targeting moieties and/or antimicrobial effectors in the compositions and methods described herein.
FIG. 8 shows illustrative hypericin and the perylenequinonoid pigments suitable for use as targeting moieties and/or antimicrobial effectors in the compositions and methods described herein.
FIG. 9 shows illustrative acridines suitable for use as targeting moieties and/or antimicrobial effectors in the compositions and methods described herein.
FIG. 10 illustrates the structure of the acridine Rose Bengal.
FIG. 11 illustrates various crown ethers suitable for use as targeting moieties and/or antimicrobial effectors in the compositions and methods described herein.
FIG. 12 illustrates the structure of cumin.
FIG. 13 illustrates an example of a targeted light-activated porphyrin we have constructed: C16-P18 comprising a porphyrin coupled to a C16 (SEQ ID NO:3) targeting sequence.
FIG. 14 schematically shows some illustrative configurations for chimeric constructs described herein. A: Shows a single targeting moiety T1 attached to a single effector E1 by a linker/spacer L. B: Shows multiple targeting moieties T1, T2, T3 attached directly to each other and attached by a linker L to a single effector E1. In various embodiments T1, T2, and T3, can be domains in a fusion protein. C: Shows multiple targeting moieties T1, T2, T3 attached to each other by linkers L and attached by a linker L to a single effector E1. In various embodiments T1, T2, and T3, can be domains in a fusion protein. D: Shows a single targeting moiety T1 attached by a linker L to multiple effectors E1, E2, and E3 joined directly to each other. E: Shows a single targeting moiety T1 attached by a linker L to multiple effectors E1, E2, and E3 joined to each other by linkers L. F: Shows multiple targeting moieties joined directly to each other and by a linker L to multiple effectors joined to each other by linkers L. G: Shows multiple targeting moieties joined to each other by linkers L and by a linker L to multiple effectors joined to each other by linkers L. In various embodiments T1, T2, and T3, and/or E1, E2, and E3 can be domains in a fusion protein. H: Illustrates a branched configuration where multiple targeting moieties are linked to a single effector. I: Illustrates a dual branched configuration where multiple targeting moieties are linked to multiple effectors. J: Illustrates a branched configuration where multiple targeting moieties are linked to multiple effectors where the effectors are joined to each other in a linear configuration.
FIG. 15 illustrates various MH-STAMPs used in Example 1. The design, sequence, and observed mass (m/z) for M8(KH)-20 (SEQ ID NOs:4, 5, and 6), BL(KH)-20 (SEQ ID 7, 8, and 9), and M8(BL)-20 (SEQ ID 10, 11, and 12).
FIGS. 16A and 16B show HPLC and MS spectra of M8(KH)-20. The quality of the completed MH-STAMP was analyzed by HPLC ( FIG. 16A ) and MALDI mass spectroscopy ( FIG. 16B ). At UV absorbance 215 nm (260 and 280 nm are also plotted), a single major product was detected by HPLC (* retention volume 11.04 mL). After fraction collection, the correct mass (m/z) for single-charged M8(KH)-20, 4884.91 (marked by *), was observed for this peak. Y-axis: 16A, mAU miliabsorbance units; 16 B, percent intensity.
FIG. 17A-17E show growth inhibitory activity of MH-STAMPs. Monocultures of S. mutans ( FIG. 17A ); P. aeruginosa ( FIG. 17B ); S. epidermidis ( FIG. 17C ); S. aureus ( FIG. 17D ); or E. coli ( FIG. 17E ); were treated with peptides (as indicated in the figure) for 10 min. Agent was then removed and fresh media returned. Culture recovery was measured over time (OD600). Plots represent the average of at least 3 independent experiments with standard deviations.
FIG. 18 illustrates the selective activity of dual-targeted and single-targeted MH-STAMPs in mixed culture. A mixture of P. aeruginosa (Pa), S. mutans (Sm), E. coli (Ec), and S. epidermidis (Se) planktonic cells were mixed with MH-STAMPs (as indicated in the figure) and treated 24 h. After incubation, cfu/mL of remaining constituent species were quantitated after plating to selective media. * indicates under 200 surviving cfu/mL recovered.
FIGS. 19A and 19B illustrate Rose Bengal ( FIG. 19A ) and synthesis scheme for C16-RB, halides and side-chains omitted for clarity ( FIG. 19B ).
FIG. 20 shows LC/MS profile C16-RB. Purity and molecular mass of C16-RB was confirmed by LC/MS. A single product was observed at 11.92 min with mass species at 1040.8 and 1560.25 daltons. Expected C16-RB mas: m/z=3118, m 2+ /z=1559, m 3+ /z=1039.
FIG. 21 illustrates activity of RB and C16-RB against single-species S. mutans biofilms. * indicates fewer than 100 cfu/mL recovered
FIG. 22 shows S. mutans -specific C16-RB activity. C16-RB, and not RB alone, preferentially eliminated S. mutans , and not other oral streptococci, after blue light illumination.



DETAILED DESCRIPTION
In various embodiments, novel “targeting” peptides are identified that specifically or preferentially bind particular microorganisms (e.g., bacteria, yeasts, fungi, etc.). These peptides can be used alone to bind/capture and thereby identify and/or isolate particular target microorganisms, or they can be attached to one or more effectors (e.g., drugs, labels, etc.) and used as targeting moieties thereby providing a chimeric moiety that preferentially or specifically delivers the effector to a target microorganism, a population of target microorganisms, a microbial film, a biofilm, and the like.
In various embodiments novel peptides having antimicrobial activity against certain bacteria, fungi, yeasts, and/or viruses and/or having activity that inhibits the growth or maintenance of biofilms comprising such microorganisms are provided. The AMPs can be used to inhibit the growth and/or proliferation of a microbial species and/or the growth and/formation and/or maintenance of a biofilm comprising the microbial species.
In certain embodiments, the targeting moieties can be attached to antimicrobial peptides to form Specifically Targeted Anti-Microbial Peptides (STAMPs). In certain embodiments attachment of one or more targeting moieties/peptides to one or more antimicrobial peptides can narrow the spectrum of activity of the AMP(s) to provide efficacy against one or a few target microorganisms without substantially disrupting the remaining microbial ecology and thereby provide increased efficacy with fewer side effects.
In certain embodiments STAMPs or effector peptides can be delivered against pathogenic bacteria by being cloned and expressed in probiotic organisms for therapeutic delivery in vivo. Recombinant expression (and overexpression) and export of antimicrobial peptides and other peptides are well documented in bacteria, including species that are also utilized as probiotics.
In various embodiments the targeting peptides, antimicrobial peptides, and/or STAMPs can be formulated individually, in combination with each other, in combination with other antimicrobial peptides, and/or in combination with various antibacterial agents to provide antimicrobial reagents and/or pharmaceuticals.
Accordingly, in certain embodiments this invention provides peptides having antimicrobial activity, compositions comprising the peptides, methods of using the peptides (or compositions thereof) to inhibit the growth of or kill a wide variety of microbial targets and methods of using the peptides (or compositions thereof) to treat or prevent microbial infections and diseases related thereto in both plants and animals.
The various peptides (targeting peptides, AMPs, STAMPs, etc.) described herein exhibit antimicrobial activity, being biostatic or biocidal against a certain microbial targets, including but not limited to, Gram-negative bacteria such as Acinetobacter baumannii, Escherichia coli, Fusobacterium nucleatum, Pseudomonas aeruginosa, Porphyromonas gingivalis ; Gram-positive bacteria such as Actinomyces naeslundii, Bacillus subtilis, Clostridium difficile, Enterococcus faecalis, Staphylococcus aureus (and MRSA), S. epidermidis, Streptococcus mutans, Streptococcus pneumoniae ; and yeast or fungi such as Aspergillus niger, Candida albicans, Malassezia furfur , and Trichophyton rubrum (see, e.g., Table 2). Significantly, various peptides described herein are biostatic or biocidal against clinically relevant pathogens exhibiting multi-drug resistance such as, for example, methicillin-resistant Staphylococcus aureus (“MRSA”).





TABLE 2



Illustrative target microorganisms and associated pathology.









Acinetobacter baumannii

Pathogenic gram-negative bacillus that is naturally sensitive

( A. baumannii )
to relatively few antibiotics.


Actinomyces naeslundii

Gram positive rod shaped bacteria that occupy the oral

( A. naeslundii )
cavity and are implicated in periodontal disease and root


caries.


Aspergillus niger

A fungal infection that often causes a black mould to appear

( A. niger )
on some fruit and vegetables but may also infect humans


through inhalation of fungal spores.


Bacteroides fragilis

Gram positive bacilli that are opportunistic human

( B. fragilis )
pathogens, causing infections of the peritoneal cavity,


gastrointestinal surgery, and appendicitis via abscess


formation, inhibiting phagocytosis. Resistant to a wide


variety of antibiotics -- β-lactams, aminoglycosides, and


recently many species have acquired resistance to


erythromycin and tetracycline.


Bacillus subtilis

Gram-positive, catalase-positive bacterium.

( B. subtilis )


Candida albicans

Causal agent of opportunistic oral and genital fungal

( C. albicans )
infections in humans.


Clostridium difficile

A gram-positive, anaerobic, spore-forming bacillus that is

( C. difficile )
responsible for the development of antibiotic-associated


diarrhea and colitis.


Corynebacterium jeikeium

Gram positive, opportunistic pathogen primarily of

( C. jeikeium )
immunocompromised (neutropenic) patients. Highly


resistant to antibiotics


Campylobacter jejuni

Gram negative cause of human gastroenteritis/food

( C. jejuni )
poisoning.


Escherichia coli

Gram negative rod-shaped bacterium commonly found in the

( E. coli )
lower intestine of warm-blooded organisms. Certain strains


cause serious food poisoning in humans.


Enterococcus faecalis

Gram-positive commensal bacterium

( E. faecalis )


Fusobacterium nucleatum

Gram negative schizomycetes bacterium often seen in

( F. nucleatum )
necrotic tissue and implicated, but not conclusively, with


other organisms in the causation and perpetuation of


periodontal disease.


Lactobacillus acidophilus

Gram-positive commensal bacterium.

( L. acidophilus )


Legionella pneumophila

Gram negative bacterium that is the causative agent of

( L. pneumophila )
legionellosis or Legionnaires' disease.

( Micrococcus luteus )
Gram positive, spherical, saprotrophic bacterium found in


M. luteus

soil, dust, water and air, and as part of the normal flora of the


mammalian skin. The bacterium also colonizes the human


mouth, mucosae, oropharynx and upper respiratory tract.


Considered an emerging nosocomial pathogen in


immunocompromised patients.


Mycobacterium smegmatis

Gram-variable (acid-fast) soil-dwelling organism utilized as

( M. smegmatis )
a proxy for Mycobacterium tuberculosis during research and


development.


Malassezia furfur

Yeast - cutaneous pathogen.

( M. furfur )

Methicillin-resistant
Any strain of Staphylococcus aureus bacteria (gram positive)


Staphylococcus aureus

that is resistant to a one or more members of a large group of

(MRSA)
antibiotics called the beta-lactams. Responsible for skin and


systemic infections.


Myxococcus xanthus

Gram negative cells that form biofilms and display primitive

( M. xanthus )
social motility and fruiting body organization.


Pseudomonas aeruginosa

Gram-negative rod. Frequent opportunistic pathogen and


P. aeruginosa

infects burn wounds. Causes ear infections in children.


Infects the lungs of cystic fibrosis patients.


Porphyromonas gingivalis

Non-motile, gram-negative, rod-shaped, anaerobic

( P. gingivalis )
pathogenic bacterium (periodontal disease)


Progeussmirabilis

Gram-negative, facultatively anaerobic bacterium. Causes

( P. mirabilis )
90% of all ‘Proteus’ infections in humans.


S. epidermidis

Gram-positive, coagulase-negative cocci. Nosocomial

( S. epidermidis )
pathogen associated with infection (biofilm) of implanted


medical device.


Streptococcus mutans

Gram-positive, facultatively anaerobic bacterium commonly

( S. mutans )
found in the human oral cavity and is a significant


contributor to tooth decay


Streptococcus pneumoniae

Gram-positive, alpha-hemolytic, bile soluble aerotolerant

( S. pneumoniae )
anaerobe. Causal agent for streptococcal pneumonia.


Treponema denticola

Gram-negative oral spirochete associated with the incidence

( T. denticola )
and severity of human periodontal disease.


Trichophyton rubrum

Most common cause of athlete's foot, jock itch and

( T. rubrum )
ringworm.
































































































The various agents described herein (targeting peptides, compound targeting peptides, antimicrobial peptides (AMPs) and/or compound AMPs, STAMPs and/or other chimeric moieties). or compositions thereof, are useful as biocidal or biostatic or fungicidal or fungistatic agents and/or virucidal agents in a wide variety of applications. For example, the agents can be used to disinfect or preserve a variety of materials including medical instruments, foodstuffs, medicaments, cosmetics and other nutrient-containing materials. Various peptides described herein are particularly useful as bacteriostatic or bactericidal agents against multi-drug-resistant pathogens such as MRSA in a variety of clinical settings.
The agents described herein, or compositions thereof, are also useful for the prophylaxis or treatment of microbial infections and diseases related thereto in both plants and animals. Such diseases include, but are not limited to, Gram-negative and Gram-positive bacterial infections, endocarditis, pneumonia and other respiratory infections, urinary tract infections, systemic candidiasis, oral mucositis, fungal infections, biofilm formation or maintenance (e.g., on medical implants), and the like.
In various embodiments, the agents described herein can be formulated individually, in combination with each other, in combination with other antimicrobial peptides, and/or in combination with various antibiotic (e.g., antibacterial) agents in “home healthcare” formulations. Such formulations include, but are not limited to toothpaste, mouthwash, tooth whitening strips or solutions, contact lens storage, wetting, or cleaning solutions, dental floss, toothpicks, toothbrush bristles, oral sprays, oral lozenges, nasal sprays, aerosolizers for oral and/or nasal application, wound dressings (e.g., bandages), and the like.
Such applications are illustrative and not limiting. Using the teachings provided herein other uses of the AMPs and compositions described herein will be recognized by one of
I. Targeting Peptides.
A) Uses of Targeting Peptides.
The novel microorganism-binding peptides (targeting peptides) described herein can be used to preferentially or specifically deliver an effector to a microorganism (e.g., a bacterium, a fungus, a protozoan, an algae, etc.), to a bacterial film, to a biofilm, and the like. The targeting peptides described herein can be used to bind to and thereby label particular targets, and/or as capture reagents to bind target microorganisms and thereby provide an indicator of the presence and/or quantity of the target microorganism(s). In certain embodiments the targeting peptide can be attached to an effector such as an epitope tag and/or a detectable label and thereby facilitate the identification of the presence and/or location, and/or quantity of the target (e.g., target organism). Thus targeting moieties are thus readily adapted for use in in vivo diagnostics, and/or ex vivo assays. Moreover, because of small size and good stability, microorganism binding peptides are well suited for microassay systems (e.g., microfluidic assays (Lab on a Chip), microarray assays, and the like).
In certain embodiments the microorganism binding peptides (targeting peptides) can be attached to an effector that has antimicrobial activity (e.g., an antimicrobial peptide, an antibacterial and/or antifungal, a vehicle that contains an antibacterial or antifungal, etc. In various embodiments these chimeric moieties can be used in vivo, or ex vivo to preferentially inhibit or kill the target organism(s).
In certain embodiments the targeting peptides can be recombinantly expressed as part of a yeast or phage tail fiber or coat protein to enhance binding of the yeast or phage to a specific bacterial Gram-designation, genus, species, or strain. Phage with expressed peptides will then display altered infection selectivity towards a designed target bacteria for use in phage therapy. Cloning the DNA encoding a peptide of interest into the major or minor coat proteins of a bacteriophage, for example in Proteins I through VIII of phages SAP-2, M13, or T7, will result in a targeted phage expressing 1-200 copies of the targeting peptide on the phage surface.
In certain embodiments the targeting peptides can be used in various pre-targeting protocols. In pre-targeting protocols, a chimeric molecule is utilized comprising a primary targeting species (e.g. a microorganism-binding peptide) that specifically binds the desired target (e.g. a bacterium) and an effector that provides a binding site that is available for binding by a subsequently administered second targeting species. Once sufficient accretion of the primary targeting species (the chimeric molecule) is achieved, a second targeting species comprising (i) a diagnostic or therapeutic agent and (ii) a second targeting moiety, that recognizes the available binding site of the primary targeting species, is administered.
An illustrative example of a pre-targeting protocol is the biotin-avidin system for administering a cytotoxic radionuclide to a tumor. In a typical procedure, a monoclonal antibody targeted against a tumor-associated antigen is conjugated to avidin and administered to a patient who has a tumor recognized by the antibody. Then the therapeutic agent, e.g., a chelated radionuclide covalently bound to biotin, is administered. The radionuclide, via its attached biotin is taken up by the antibody-avidin conjugate pretargeted at the tumor. Examples of pre-targeting biotin/avidin protocols are described, for example, in Goodwin et al., U.S. Pat. No. 4,863,713; Goodwin et al. (1988) J. Nucl. Med. 29: 226; Hnatowich et al. (1987) J. Nucl. Med. 28: 1294; Oehr et al. (1988) J. Nucl. Med. 29: 728; Klibanov et al. (1988) J. Nucl. Med. 29: 1951; Sinitsyn et al. (1989) J. Nucl. Med. 30: 66; Kalofonos et al. (1990) J. Nucl. Med. 31: 1791; Schechter et al. (1991) Int. J. Cancer 48:167; Paganelli et al. (1991) Cancer Res. 51: 5960; Paganelli et al. (1991) Nucl. Med. Commun. 12: 211; Stickney et al. (1991) Cancer Res. 51: 6650; and Yuan et al. (1991) Cancer Res. 51:3119.
It will be recognized that the tumor-specific antibody used for cancer treatments can be replaced with a microorganism binding peptide of the present invention and similar pre-targeting strategies can be used to direct labels, antibiotics, and the like to the target organism(s).
Three-step pre-targeting protocols in which a clearing agent is administered after the first targeting composition has localized at the target site also have been described. The clearing agent binds and removes circulating primary conjugate which is not bound at the target site, and prevents circulating primary targeting species (antibody-avidin or conjugate, for example) from interfering with the targeting of active agent species (biotin-active agent conjugate) at the target site by competing for the binding sites on the active agent-conjugate. When antibody-avidin is used as the primary targeting moiety, excess circulating conjugate can be cleared by injecting a biotinylated polymer such as biotinylated human serum albumin. This type of agent forms a high molecular weight species with the circulating avidin-antibody conjugate which is quickly recognized by the hepatobiliary system and deposited primarily in the liver.
Examples of these protocols are disclosed, e.g., in PCT Application No. WO 93/25240; Paganelli et al. (1991) Nucl. Med. Comm., 12: 211-234; Oehr et al. (1988) J. Nucl. Med., 29: 728-729; Kalofonos et al. (1990) J. Nucl. Med., 31: 1791-1796; Goodwin et al. (1988) J. Nucl. Med., 29: 226-234; and the like).
These applications of microorganism binding peptides of this invention are intended to be illustrative and not limiting. Using the teaching provided herein, other uses will be recognized by one of skill in the art.
B) Illustrative Novel Targeting Peptides.
In certain embodiments, the targeting moiety comprises one or more targeting peptides that bind particular bacteria, fungi, and/or yeasts, and/or algae, and/or viruses and/or that bind particular groups of bacteria, and/or groups of fungi, and/or groups of yeasts, and/or groups of algae.
In certain embodiments the targeting peptides include peptides comprising or consisting of one or more of the amino acid sequences shown in Table 3 (SEQ ID NOs:13-1566). In various embodiments the peptides include peptides comprising or consisting of the retro, inverso, retro-inverso, and/or beta form of one or more of the amino acid sequences shown in Table 3. Also contemplated are circular permutations of these sequences as well as peptides comprising or consisting of the retro, inverso, retro-inverso, and/or beta form of such circular permutations.
It will also be recognized, that in certain embodiments, any peptide or compound AMP described herein can be circularized.
In various embodiments the peptides can optionally bear one or more protecting groups, e.g., and the amino and/or carboxyl termini, and/or on side chains.
Also contemplated are peptides comprising one, two, three four, or five conservative substitutions of these amino acid sequences.





TABLE 3



Illustrative list of novel targeting peptides.









SEQ ID

ID
Target(s)
Targeting Peptide Sequence
NO








1T-3

S. mutans

VLGIAGGLDAYGELVGGN
13



S. gordonii






1T-4

S. mutans

LDAYGELVGGN
14



S. gordonii






S. sanguinis






S. oralis






V. atypica






L. casei






1T-6

S. mutans

KFINGVLSQFVLERK
15



1T-7

M. xanthus

SQRIIEPVKSPQPYPGFSVS
16



1T-8

M. xanthus

FSVAACGEQRAVTFVLLIEDLI
17



1T-9

M. xanthus

WAWAESPRCVSTRSNIHALAFRVEVAA
18



LT




1T-10

M. xanthus

SPAGLPGDGDEA
19



1T-11

S. mutans

RISE
20



S. epidermidis






P. aeruginosa






1T-12

C. xerosis

FGNIFKGLKDVIETIVKWTAAK
21



C. striatum






S. epidermidis






S. mutans






1T-13

S. aureus

FRSPCINNNSLQPPGVYPAR
22



S. epidermidis






P. aeruginosa






1T-14

S. mutans

ALAGLAGLISGK
23



S. aureus






S. epidermidis






C. xerosis






1T-15

S. mutans

DVILRVEAQ
24



1T-16

P. aeruginosa

IDMR
25



1T-17

S. mutans

NNAIVYIS
26



1T-18

S. aureus

YSKTLHFAD
27



S. epidermidis






C. striatum






P. aeruginosa






1T-19

S. aureus

PGAFRNPQMPRG
28



S. epidermidis






P. aeruginosa






1T-20

S. mutans

PALVDLSNKEAVWAVLDDHS
29



P. aeruginosa






1T-21

S. mutans

YVEEAVRAALKKEARISTEDTPVNLPSF
30



P. aeruginosa

DC




1T-22

S. epidermidis

VPLDDGTRRPEVARNRDKDRED
31



P. aeruginosa






1T-23

S. mutans

PALVDLSNKEAVWAVLDDHS
32



P. aeruginosa






1T-24

P. aeruginosa

EEAEEKLAEVSQAVKRLVR
33



1T-25

S. aureus

VGLDVSVLVLFFGLQLLSVLLGAMIR
34



S. epidermidis






C. xerosis






C. striatum






P. aeruginosa






1T-26

S. mutans

LTILPTTFFAIIVPILAVAFIAYSGFKIKGI
35



S. aureus

VEHKDQW




S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-27

S. mutans

ALFVSLEQFLVVVAKSVFALCHSGTLS
36



S. aureus






S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-28

P. aeruginosa

VSRDEAMEFIDREWTTLQPAGKSHA
37



1T-29

S. mutans

GSVIKKRRKRMSKKKHRKMLRRTRVQ
38



S. aureus

RRKLGK




S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-30

S. aureus

GKAKPYQVRQVLRAVDKLETRRKKGG
39



S. epidermidis

R




C. xerosis






C. striatum






P. aeruginosa






1T-31

S. mutans

NATGTDIGEVTLTLGRFS
40



P. aeruginosa






1T-32

S. mutans

VSFLAGWLCLGLAAWRLGNA
41



1T-33

S. aureus

VRTLTILVIFIFNYLKSISYKLKQPFENNL
42



S. epidermidis

AQSMISI




C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-34

S. aureus

AFWLNILLTLLGYIPGIVHAVYIIAKR
43



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-35

P. aeruginosa

EICLTLVFPIRGSYSEAAKFPVPIHIVEDG
44



TVELPK




1T-36

S. aureus

VYRHLRFIDGKLVEIRLERK
45



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-37

S. mutans

YIVGALVILAVAGLIYSMLRKA
46



S. aereus






S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-38

S. mutans

VMFVLTRGRSPRPMIPAY
47



S. aereus






S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-39

S. mutans

FGFCVWMYQLLAGPPGPPA
48



P. aeruginosa






1T-40

S. mutans

QRVSLWSEVEHEFR
49



P. aeruginosa






1T-41

S. mutans

KRGSKIVIAIAVVLIVLAGVWVW
50



S. aureus






S. epidermidis






C. jeikeium






C. striatum






P. aeruginosa






1T-42

S. aureus

TVLDWLSLALATGLFVYLLVALLRADR
51



S. epidermidis

A




C. xerosis






C. striatum






P. aeruginosa






1T-43

C. jeikium

DRCLSVLSWSPPKVSPLI
52



P. aeruginosa






1T-44

S. mutans

DPALADFAAGMRAQVRT
53



S. aureus






S. epidermidis






C. jeikeium






C. striatum






P. aeruginosa






1T-45

S. aureus

WTKPSFTDLRLGFEVTLYFANR
54



S. epidermidis






C. striatum






P. aeruginosa






1T-46

S. aureus

FSFKQRVMFRKEVERLR
55



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-47

S. mutans

VIKISVPGQVQMLIP
56



S. epidermidis






P. aeruginosa






1T-48

S. aureus

KLQVHHGRATHTLLLQPPLCAPGTIR
57



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-49

S. aureus

SLVRIHDQQPWVTRGAFIDAARTCS
58



S. epidermidis






C. jeikeium






P. aeruginosa






1T-50

P. aeruginosa

HSDEPIPNILFKSDSVH
59



1T-51

S. aureus

GKPKRMPAEFIDGYGQALLAGA
60



P. aeruginosa






1T-52

S. aureus

DEYPAKLPLSDKGATEPRRH
61



C. xerosis






P. aeruginosa






1T-53

P. aeruginosa

SDILAEMFEKGELQTLVKDAAAKANA
62



1T-54

S. epidermidis

RWVSCNPSWRIQ
63



C. xerosis






C. striatum






P. aeruginosa






1T-55

C. xerosis

NHKTLKEWKAKWGPEAVESWATLLG
64



P. aeruginosa






1T-56

C. xerosis

LALIGAGIWMIRKG
65



P. aeruginosa






1T-57

P. aeruginosa

RLEYRRLETQVEENPESGRRPMRG
66



1T-58

P. aeruginosa

CDDLHALERAGKLDALLSA
67



1T-59

S. aureus

AVGNNLGKDNDSGHRGKKHRKHKHR
68



S. epidermidis






P. aeruginosa






1T-60

S. aureus

YLTSLGLDAAEQAQGLLTILKG
69



S. epidermidis






C. jeikeium






C. striatum






P. aeruginosa






1T-61

P. aeruginosa

HATLLPAVREAISRQLLPALVPRG
70



1T-62

S. epidermidis

GCKGCAQRDPCAEPEPYFRLR
71



P. aeruginosa






1T-63

S. aureus

EPLILKELVRNLFLFCYARALR
72



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-64

S. aureus

QTVHHIHMHVLGQRQMHWPPG
73



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-65

S. mutans

HARAAVGVAELPRGAAVEVELIAAVRP
74



S. aureus






S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-66

S. mutans

DTDCLSRAYAQRIDELDKQYAGIDKPL
75



S. aureus






S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-67

S. aureus

GQRQRLTCGRVSGCSEGPSREAAR
76



S. epidermidis






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-68

S. mutans

GGTKEIVYQRG
77



S. aureus






C. jeikeium






C. xerosis






C. striatum






P. aeruginosa






1T-69

S. mutans

ILSQEADRKKLF
78



P. aeruginosa






1T-70

S. aureus

NRQAQGERAHGEQQG
79



C. jeikeium






P. aeruginosa






1T-71

P. aeruginosa

KIDTNQWPPNKEG
80



1T-72

P. aeruginosa

EPTDGVACKER
81



1T-73

S. pneumoniae

GWWEELLHETILSKFKITKALELPIQL
82



1T-74

S. pneumoniae

DIDWGRKISCAAGVAYGAIDGCATTV
83



1T-75

S. pneumoniae

GVARGLQLGIKTRTQWGAATGAA
84



1T-76

S. pneumoniae

EMRLSKFFRDFILWRKK
85



1T-77

S. pneumoniae

EMRISRIILDFLFLRKK
86



1T-78

S. pneumoniae

FFKTIFVLILGALGVAAGLYIEKNYIDK
87



1T-79

S. pneumoniae

FGTPWSITNFWKKNFNDRPDFDSDRRR
88



Y




1T-80

S. pneumoniae

GGNLGPGFGVIIP
89



1T-81

S. pneumoniae

AIATGLDIVDGKFDGYLWA
90



1T-82

S. pneumoniae

FGVGVGIALFMAGYAIGKDLRKKFGKS
91



C




1T-83

S. pneumoniae

QKPRKNETFIGYIQRYDIDGNGYQSLPC
92



PQN




1T-84

S. pneumoniae

FRKKRYGLSILLWLNAFTNLVNSIHAFY
93



MTLF




1T-85

A. naeslundii

VMASLTWRMRAASASLPTHSRTDA
94



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-86

S. mitis

HRKNPVLGVGRRHRAHNVA
95



S. oralis






S. salivarious






1T-87

S. mitis

EAVGQDLVDAHHP
96



S. mutans






S. oralis






1T-89

S. mitis

HEDDKRRGMSVEVLGFEVVQHEE
97



S. mutans






1T-90

S. gordonii

RNVIGQVL
98



S. mitis






S. mutans






S. oralis






S. sanguinis






1T-91

S. mitis

TSVRPGAAGAAVPAGAAGAAGAGWR
99



S. mutans

WP




S. oralis






S. sanguinis






1T-92

S. mitis

GQDEGQRRAGVGEGQGVDG
100



S. mutans






1T-93

S. epidermidis

AMRSVNQA
101



S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-94

S. mitis

DQVAHSGDMLVQARRRDS
102



S. mutans






S. oralis






1T-95

S. gordonii

GHLLRVGGRVGGVGGVAGACAQPFGG
103



S. mitis

Q




S. mutans






S. oralis






S. sanguinis






1T-96

S. gordonii

VAGACAQPFGGQ
104



S. mitis






S. mutans






S. oralis






S. sanguinis






1T-97

A. naeslundii

GVAERNLDRITVAVAIIWTITIVGLGLV
105



F. nucleatum

AKLG




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-98

A. naeslundii

VRSAKAVKALTAAGYTGELVNVSGGM
106



F. nucleatum

KAWLGQ




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-99

S. gordonii

MKAWLGQ
107



S. mitis






S. mutans






S. oralis






S. sanguinis






1T-100

S. gordonii

LDPLEPRIAPPGDRSHQGAPACHRDPLR
108



S. mitis

GRSARDAER




S. mutans






1T-101

A. naeslundii

RLRVGRATDLPLTSFAVGVVRNLPDAP
109



P. gingivalis

AH




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-102

A. naeslundii

WKRLWPARILAGHSRRRMRWMVVWR
110



F. nucleatum

YFAAT




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-103

A. naeslundii

AQFYEAIITGYALGAGQRIGQL
111



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-104

S. mitts

RAVAAHLQGRHEIGHQVRRQRHGQR
112



1T-105

S. epidermidis

GEGLPPPVLHLPPPRMSGR
113



S. gordonii






S. mitis






S. mutans






S. oralis






1T-106

S. gordonii

DALRRSRSQGRRHR
114



S. mitis






S. mutans






S. oralis






S. salivarious






1T-107

A. naeslundii

SPVPRFTAVGGVSRGSP
115



S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-108

S. gordonii

WGPLGPERPLW
116



S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-109

A. naeslundii

VTTNVRQGAGS
117



S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-110

A. naeslundii

LAAKTAVCVGRAFM
118



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-111

A. naeslundii

GRLSRREEDPATSIILLRGAYRMAVF
119



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-112

S. gordonii

SDNDGKLILGTSQ
120



1T-113

S. mitis

HGAHQRTGQRLHEIHRGRTVSGCRQNP
121



VAGVDPDEHR




1T-114

A. naeslundii

RQAPGPGLVTITAACSAPGSRSR
122



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-115

A. naeslundii

LLIERFSNHH
123



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-116

A. naeslundii

MILHRRRDR
124



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-117

S. mutans

GPGVVGPAPFSRLPAHALNL
125



1T-118

A. naeslundii

TASPPAPSDQGLRTAFPATLLIALAALA
126



F. nucleatum

RISR




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-119

S. gordonii

SPATQKAPTRAQPSRAPVQDCGDGRPT
127



S. mitis

AAPDDVERLSPR




S. mutans






S. oralis






1T-120

A. naeslundii

DVRDRVDLAGADLCAAHATR
128



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-121

S. gordonii

FAKETGFGIGGAQEGWWIIADIYGPNPF
129



S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-122

S. mitts

GAIPDPVTHRVDWEEDHQTRPSR
130



1T-123

S. gordonii

LVRRNAVAGRSDGLAGAEQLDLVRLQ
131



GVL




1T-124

S. mitts

LFDERNKIA
132



S. mutans






S. oralis






1T-125

S. epidermidis

DAITGGNPPLSDTDGLRP
133



S. gordonii






S. mutans






S. oralis






1T-126

S. gordonii

QGLARPVLRRIPL
134



S. mitis






S. mutans






1T-127

A. naeslundii

YDPVPKRKNKNSEGKREE
135



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-128

A. naeslundii

SGSAIRMLEIATKMLKR
136



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-129

A. naeslundii

YDKYIKYLSIQPPFIVYFI
137



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-130

A. naeslundii

QKIIDMSKFLFSLILFIMIVVIYIGKSIGG
138



F. nucleatum

YSAIVSSIMLELDTVLYNKKIFFIYK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-131

A. naeslundii

DEVWKMLGI
139



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-132

A. naeslundii

YSKKLFEYFYFIIFILIRYLIFYKIIQNKNY
140



F. nucleatum

YINNIAYN




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-133

A. naeslundii

YFIKDDNEALSKDWEVIGNDLKGTIDK
141



P. gingivalis

YGKEFKVR




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-134

A. naeslundii

SRLVREIKKKCRKS
142



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-135

A. naeslundii

FESLLPQATKKIVNNKGSKINKIF
143



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-136

A. naeslundii

ELLTQIRLALLYSVNEW
144



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-137

A. naeslundii

PLNFYRAVKENRLPLSEKNINDFTNIKL
145



F. nucleatum

KVSPKLINLLQESSIFYNFSPKKRNTN




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-138

A. naeslundii

YPNEYCIFLENLSLEELKEIKAINGETLN
146



F. nucleatum

LEEIINERKNLKD




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-139

A. naeslundii

AVAGAAVGALLGNDARSTAVGAAIGG
147



S. gordonii

ALGAGAGELTKNK




S. mitis






S. mutans






S. oralis






1T-140

A. naeslundii

IKGTIAFVGEDYVEIRVDKGVKLTFRKS
148



F. nucleatum

AIANVINNNQQ




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-141

F. nucleatum

KKFIILLFILVQGLIFSATKTLSDIIAL
149



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-142

A. naeslundii

FTQGIKRIVLKRLKED
150



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-143

A. naeslundii

MPKRHYYKLEAKALQFGLPFAYSPIQL
151



F. nucleatum

LK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-144

A. naeslundii

IIELHPKSWTQDWRCSFL
152



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-145

S. mitts

VEAGKRNISLENIEKISKGLGISISELFKY
153



S. mutans

IEEGEDKIG




S. oralis






1T-146

A. naeslundii

RNSADNQTKIDKIRIDISLWDEHLNIVK
154



F. nucleatum

QGK




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-147

A. naeslundii

GVENRRFYERDVSKVSMNITSEAVAPR
155



F. nucleatum

GGSK




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-148

A. naeslundii

IVELDDTTILERALSMLGEANA
156



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-149

A. naeslundii

SVRAVKPIDETVARHFPGDFIVN
157



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-150

A. naeslundii

YINRRLKKAFSDADIKEAPAEFYEELRR
158



F. nucleatum

VQYV




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-151

A. naeslundii

SVRAVKPIDEIVAWHFPGDFIVN
159



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-152

A. naeslundii

YVSADESAYNHIVTDDIPLADRRIEAVQ
160



F. nucleatum

Q




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-153

A. naeslundii

YIACPGYFY
161



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-154

P. gingivalis

YFSFLEIVGMARR
162



1T-155

A. naeslundii

LKLAFGVYPFQANISQSDTAVSERNVL
163



F. nucleatum

WR




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-156

A. naeslundii

GRFQISIRGEEKSKVKVQGKGTFTDRNT
164



F. nucleatum

T




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-157

A. naeslundii

RRFRKTTENREKSKNKKAVLGLSTTST
165



F. nucleatum

ASY




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-158

A. naeslundii

WENKPSPLGSIKKLQGLVYRLIGYRHF
166



F. nucleatum

WV




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-159

P. gingivalis

IFSLHHFALICSEMGTFAVSKRAKYKWE
167



VL




1T-160

A. naeslundii

AQYKYINKLLN
168



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-161

A. naeslundii

NKVLQVEVMWDGSVVGRPAGVISIKSS
169



F. nucleatum

KKG




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-162

A. naeslundii

QKAKEESDRKAAVSYNGFHRVNVVSIP
170



F. nucleatum

K




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-163

A. naeslundii

MENILIYIPMVLSPFGSGILLFLGKDRRY
171



F. nucleatum

ML




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-164

A. naeslundii

KKSHSQGKRKLKDLNSAYKIDNQLHYA
172



F. nucleatum

LR




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-165

A. naeslundii

CYDSFDFSIFVTFANRMKLSVGS
173



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. Mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-166

A. naeslundii

AQSAGQIKRKSKVRIHV
174



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-167

A. naeslundii

SRMSEHSPAGLVFEVGPMDKGSFIILDS
175



F. nucleatum

YHPTVKK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-168

A. naeslundii

ELHRIMSTEKIGAVTKMNFDTAPIMSILP
176



F. nucleatum

IDIYPKEVGIGS




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-169

A. naeslundii

FARVRRLHQNRILTQPLTNLKYCLRQPI
177



F. nucleatum

YSD




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-170

P. gingivalis

AYGKVFSMDIMLSENDKLIVLRISHESA
178



WH




1T-171

A. naeslundii

SVRAVKPIDKTVARHFPGDFIVN
179



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-172

A. naeslundii

FEGLKNLLGDDII
180



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-173

A. naeslundii

LFRKEDQEHVLL
181



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-174

A. naeslundii

SGGSDTDGSSSGEPGSHSGDL
182



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-175

A. naeslundii

GEPGSHSGDL
183



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-176

A. naeslundii

PVGDIMSGFLRGANQPRFLLDHISFGS
184



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-177

P. gingivalis

GTNVPTQILGYSREERFDYEPAPEQR
185



S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-178

A. naeslundii

LLASHPERLSLGVFFVYRVLHLLLENT
186



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-179

A. naeslundii

TCYPLIQRKTDRAYEA
187



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-180

A. naeslundii

VVFGGGDRLV
188



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-181

A. naeslundii

YGKESDP
189



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-182

A. naeslundii

LTASICRQWNDNSTPYQR
190



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-183

A. naeslundii

PLRSFVAEKAEHAFRVVRIADFDFGHS
191



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-184

A. naeslundii

ALLVLNLLLMQFFFGKNIVI
192



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-185

A. naeslundii

HYHFLLEFGFHKGDYLE
193



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-188

S. sanguinis

HRKDVYKK
194



1T-190

A. naeslundii

IQIIVNAFVEKDKTGAVIEVLYASNNHE
195



F. nucleatum

KVKAKYEELVAIS




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-192

S. sanguinis

ILVLLALQVELDSKFQY
196



1T-193

S. sanguinis

LMIFDKHANLKYKYGNRSFGVEAIM
197



1T-195

S. mutans

AASGFTYCASNGVWHPY
198



1T-196

F. nucleatum

KPEKEKLDTNTLMKVVNKALSLFDRLL
199



S. sanguinis

IKFGA




1T-197

A. naeslundii

TEILNFLITVCADRENWKIKHGLSDSVL
200



F. nucleatum

LIFFARFTGAEYW




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-198

P. gingivalis

MPVSKKRYMLSSAYATALGICYGQVAT
201



S. epidermidis

DEKESEITAIPDLLDYLSVEEYLL




S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-199

S. sanguinis

RAGRIKKLSQKEAEPFEN
202



1T-200

A. naeslundii

MRFKRFDRDYALSGDNVFEVLTASCDV
203



F. nucleatum

IERNLSYREMCGLMQ




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-201

S. sanguinis

KRKHENVIVAEEMRVIKN
204



1T-202

A. naeslundii

LCRLEKLCKQFLRQDKVVTYYLMLPYK
205



F. nucleatum

RAIEAFYQELKERS




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-203

A. naeslundii

YPFCLATVDHLPEGLSVTDYERVQRLV
206



F. nucleatum

SQFLLNKEER




P. gingivalis






S. epidermidis






S. gordonii






S. Mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-207

F. nucleatum

SPLEKYGTGSMTALTFLLGCCLLVLSKK
207



S. sanguinis

SR




1T-208
Unanalyzed
KRKRWAILTLFLAGLGAVGIVLATF
208



1T-215

S. sanguinis

VCFKDISVFLSPFRGQEVLFCGKAKHSL
209



IYVIGT




1T-216

S. sanguinis

FFLNVIAIRIPHF
210



1T-217

F. nucleatum

MLSNVLSRSVVSPNVDIPNSMVILSPLLI
211



S. sanguinis

SISNYH




1T-218

F. nucleatum

KLIFAALGLVFLLIGLRDSRSK
212



S. sanguinis






1T-219

S. sanguinis

RNINVSATFITEKSLV
213



1T-221

A. naeslundii

DIGRIIGKKGRTITAIRSIVYSVPTQGKK
214



F. nucleatum

VRLVIDEK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-222

F. nucleatum

RIEASLISAIMFSMFNAIVKFLQK
215



S. sanguinis






1T-223

A. naeslundii

NQKMEINSMTSEKEKMLAGHFHNEAN
216



F. nucleatum

FAVIFKYSLFYNFF




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-225

A. naeslundii

RRSLGNSASFAEWIEYIRYLHYIIRVQFI
217



F. nucleatum

HFFSKNKKI




P. gingivalis






S. epidermidis






S. gordonii






S. Mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-226

A. naeslundii

KLQEKQIDRNFERVSGYSTYRAVQAAK
218



F. nucleatum

AKEKGFISLEN




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-228

A. naeslundii

IFKLFEEHLLYLLDAFYYSKIFRRLKQGL
219



F. nucleatum

YRRKEQPYTQDLFRIVI




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-230

A. naeslundii

EFLEKFKVLKQPRKANNISKNRVAMIFL
220



F. nucleatum

TIHKSRGFLSSPY




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-233

A. naeslundii

TDQELEHLIVTELESKRLDFTYSKDITEF
221



P. gingivalis

FDEAFPEYDQNY




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-234

A. naeslundii

DNFYLILKMEERGKSKKTSQTRGFRAFF
222



F. nucleatum

DIIRKKIKKEDGK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-237

S. sanguinis

EDPVPNHFTLRRNKKEKPSKS
223



1T-238

A. naeslundii

IFNRRKFFQYFGLSKEAMVEHIQPFILDI
224



F. nucleatum

WQIHLF




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-239

A. naeslundii

ADDLLNKRLTDLIMENAETVKTIDLDN
225



S. gordonii

SD




S. mitis






S. mutans






S. oralis






S. sanguinis






1T-240

A. naeslundii

VILGNGISNIAQTLGQLPNIAWVWIYMV
226



F. nucleatum

LIAALLEESNVC




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-242

F. nucleatum

KQVQNTTLIICGTVLLGILFKSYLKSQKS
227



S. sanguinis

V




1T-243

A. naeslundii

SENIARFAAAFENEQVVSYARWFRRSW
228



P. gingivalis

RGSGSSSRF




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-248

S. sanguinis

IGGALNSCG
229



1T-249

F. nucleatum

VFSVLKHTTWPTRKQSWHDFISILEYSA
230



S. sanguinis

FFALVIFIFDKLLTLGLAELLKRF




1T-250

S. mitis

LVQGDTILIENHVGTPVKDDGKDCLIIR
231



S. mutans

EADVLAVVND




S. oralis






1T-252

F. nucleatum

MKKNLKRFYALVLGFIIGCLFVSILIFIG
232



S. sanguinis

Y




1T-253

A. naeslundii

KTKESLTQQEKKFLKDYDRKSLHHFRD
233



F. nucleatum

ILTYCFILDKLTNK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-256

S. sanguinis

KGKSLMPLLKQINQWGKLYL
234



1T-257

A. naeslundii

IILAKAADLAEIERIISEDPFKINEIANYDI
235



F. nucleatum

IEFCPTKSSKAFEKVLK




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-258

A. naeslundii

TINIDDKVLDYLKKINSKAITIDLIGCAS
236



F. nucleatum






P. gingivalis






T. denticola






S. mitis






S. mutans






S. oralis






1T-259

F. nucleatum

EKLKKILLKLAVCGKAWYTL
237



P. gingivalis






T. denticola






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-260

A. naeslundii

NILYFIHDENQWEPQKAEIFRGSIKHCA
238



P. gingivalis

WLSS




S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-261

F. nucleatum

SFEKNKIENNLKIAQAYIYIKPKPRICQA
239



S. mutans






S. oralis






S. sanguinis






1T-262

A. naeslundii

LSLPLIVLTKSI
240



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-263

A. naeslundii

FIAVSFTGNPATFKLVIGCKADN
241



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. oralis






S. salivarius






S. sanguinis






1T-264

S. sanguinis

LEGKFYMAEDFDKTPECFKDYV
242



1T-265

A. naeslundii

GMFENLLMINFQIMNDLKIEIVVKDRIC
243



F. nucleatum

AV




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-266

S. sanguinis

RAGTWLVVDEIR
244



1T-267

A. naeslundii

RIKEERKNRSYKFFIWRLFDEKTGFI
245



F. nucleatum






P. gingivalis






T. denticola






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-268

F. nucleatum

PITPKKEKCGLGTYAPKNPVFSKSRV
246



S. mutans






S. oralis






S. sanguinis






1T-269

F. nucleatum

PLYVAAVEKINTAKKH
247



S. mutans






S. oralis






S. sanguinis






1T-270

F. nucleatum

VHEFDIQKILQNR
248



S. mutans






S. oralis






S. sanguinis






1T-271

A. naeslundii

FLIQKFLLIKTFPPYRKKYVVIVSQTGTA
249



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-272

F. nucleatum

QLAPIDKQLKAVKKIAFYESESTAAKAV
250



S. mutans

TVA




S. oralis






S. sanguinis






1T-273

F. nucleatum

YNEPNYKWLESYKIYKQRCEDRTGMY
251



P. gingivalis

YTEET




T. denticola






S. mitis






S. mutans






S. oralis






1T-274

F. nucleatum

ETTTEINAIKLHRIKQRSPQGTRRVN
252



S. mutans






S. oralis






S. sanguinis






1T-275

A. naeslundii

QVLKNFSISRRYKINNPFFKILLFIQLRTL
253



F. nucleatum






P. gingivalis






T. denticola






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-276

A. naeslundii

ILTLLILGSIGFFILKIKLKLGRF
254



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-277

A. naeslundii

IYYMRFVNKPLEKTFFKI
255



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-278

A. naeslundii

SINSSAGIQPHCLSSSFVLRTKHCFY
256



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-279

A. naeslundii

FVLRTKHCFY
257



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-280

A. naeslundii

TNNKNKVIIKAIKFKNKDFINLDLFIYRR
258



F. nucleatum






P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-281

A. naeslundii

KYEKLTKENLFIRNSGNMCVFIYFLFFG
259



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-282

F. nucleatum

ISLVFPAYT
260



P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-283

A. naeslundii

LCTKLEDKQRGRIPAELFIISPIKILERND
261



F. nucleatum

AL




P. gingivalis






T. denticola






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-284

A. naeslundii

FQYYFSLKRV
262



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-285

A. naeslundii

FFPYYLADFYKQLKFLNEYQTKNKDKV
263



F. nucleatum

VEFK




P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-286

S. sanguinis

LGFFNNKADLVKADTERDNRIVISSLKIK
264



DL




1T-287

P. gingivalis

KGYPLPFQYRLNNH
265



T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-288

F. nucleatum

RWVGGEPSADIYLSAKDTKT
266



S. gordonii






S. salivarius






S. sanguinis






1T-289

F. nucleatum

EPSADIYLSAKDTKT
267



P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. sanguinis






1T-290

A. naeslundii

IINQLNLILLRLMEILIL
268



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-291

A. naeslundii

DMKIIKLYIKILSFLFIKYCNKKLNSVKL
269



F. nucleatum

KA




P. gingivalis






T. denticola






S. mitis






S. mutans






S. oralis






1T-292

A. naeslundii

IINQLNLILLRLMEILIL
270



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-293

A. naeslundii

HVEDCFLLSNARTTAIHGRANPARGEPR
271



F. nucleatum

TRSE




P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarious






S. sanguinis






1T-294

T. denticola

YDKIADGVFKIGKRGVL
272



1T-295

S. mitis

KYKLKKIIL
273



S. salivarious






S. sanguinis






1T-296

A. naeslundii

EYSQQSFKAKPCSERGVLSP
274



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-297

A. naeslundii

RSLRLNNALTKLPKLWYNRIKEAFYAY
275



F. nucleatum

NDYDK




T. denticola






S. mitis






S. mutans






S. oralis






1T-298

A. naeslundii

ILNKKPKLPLWKLGKNYFRRFYVLPTFL
276



F. nucleatum

A




P. gingivalis






T. denticola






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-299

A. naeslundii

SMLTSFLRSKNTRSLKMYKDVHF
277



F. nucleatum






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-300

A. naeslundii

PLIISKAQIKMSGDILGSCFKLFYLRPFF
278



F. nucleatum






P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-301

F. nucleatum

SKLPRVLDASLKL
279



S. gordonii






S. sanguinis






1T-302

A. naeslundii

IIIILPKIYLVCKTV
280



P. gingivalis






S. epidermidis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-303

A. naeslundii

LDYENMDCKKRIRI
281



F. nucleatum






P. gingivalis






S. gordonii






S. mitis






S. mutans






S. oralis






S. salivarius






S. sanguinis






1T-304

P. gingivalis

STAGEASRRTASEASRRTAAKLRG
282



TT-305

F. nucleatum

ARNALNMRDVPVDAAIIGIIDGMDEE
283



TT-306

F. nucleatum

KILNEAEGKLLKVIEKNGEIDIEEI
284



TT-307

F. nucleatum

NGDKKAKEELDKWDEVIKELNIQF
285



TT-308

F. nucleatum

GLVIIPNLIALIILFSQVRQQTKDYFSNPK
286



LSSR




TT-309

F. nucleatum

EPLPLTKYDKKDTEMKKVFKEILAGKV
287



GYEKEEE




TT-310

F. nucleatum

TKLKKNNKLLSAKKENTLHTKDK
288



TT-311

S. mutans

AIFDAMHNL
289



S. sobrinus






PVCFBP

P. fluorescens

DLys-Dorn-Gly-DThr-Thr-Gln-Gly-DSer-
290

2461

cDOrn




CHA0

P. fluorescens

Asp-DOrn-Lys-c(Thr-Ala-Ala-DOrn-Lys)
291



CFBP2461

P. putida

Asp-Lys-DAsp-Ser-DThr-DAla-Thr-DLys-
292



cOrn




NCPPB2192

P. tolaasii

DSer-Lys-Ser-DSer-Thr-DSer-Orn-Thr-
293



DSer-cDOrn




PyC-E

P. aeruginosa

DSer-Arg-DSer-Orn-c(Lys-Orn-Thr-Thr)
294



PyR

P. aeruginosa

DSer-Dab-Orn-DGln-Gln-DOrn-G1y
295



PyPa TII

P. aeruginosa

DSer-DOrn-Orn-Gly-DThr-Ser-cOrn
296



Py Pap

P. aptata

DAla-Lys-Thr-DSer-Orm-cOrn
297



Py Pau

P. aureofaciens

DSer-DOrn-Gly-DThr-Thr-Gln-Gly-DSer-
298



cDOrn




Ps

P. fluorescens

Lys-DAsp-Ala-DThr-Ala-cDOrn
299



Py I-III

P. fluorescens

Asn-DOrn-Lys-c(Thr-DAla-DAla-DOrn-
300



Lys)




Py Gm

P. fluorescens

DAla-Lys-Gly-Gly-Asp-DGln-DSer-Ala-
301



DAla-DAla-Ala-cOrn




Py Pf 12

P. fluorescens

DSer-Lys-Gly-Orn-DSer-Ser-Gly-c(Lys-
302



DOrn-Glu-Ser)




Py Pf

P. fluorescens

c(DSer-Dab)-Gly-Ser-Asp-Ala-Gly-DAla-
303

2798

Gly-cOrn




Py Pf

P. fluorescens

Ser-Lys-Gly-Orn-c(Lys-DOrn-Ser)
304

13525






Py Pf

P. fluorescens

DAla-DLys-Gly-Gly-Asp-DGln-Dab-Ser-
305

17400

DAla-cOrn




Py 51W

P. fluorescens

DAla-DLys-G1y-Gly-DAsp-DGln-DSer-Ala-
306



Gly-DThr-cOrn




Py 9AW

P. fluorescens

DSer-Lys-His-DThr-Ser-cOrn
307



Ps A225

P. fluorescens

DSer-DAla-DOrn-Gly-c(DSer-DAsp-DSer-
308



DThr)




Py Pf 1.3

P. fluorescens

DAla-DLys-Gly-Gly-Asp-c(DGln-Dab)-Gly-
309



Ser-cOrn




Py Pf

P. fluorescens

DSer-Lys-Gly-Orn-Ser-DSer-Gly-c(Lys-
310

18.1

DOrn-Ser)




Py Pf

P. fluorescens

DSer-DOrn-Ala-Gly-DThr-Ala-cOrn
311

PL7






Py Pf

P. fluorescens

DLys-DOrn-Ala-Gly-DThr-Ser-cOrn
312

PL8






Py Pf

P. fluorescens

DSer-DSer-Orn-DSer-DSer-c(DSer-Orn-
313

BTP7

Lys-Lys)




Ps 589A

P. putida

Asp-Lys-Asp-DSer-Thr-DAla-DGlu-DSer-
314



cOrn




Py Pp 1,2

P. putida

Ser-Thr-DSer-Orn-Asp-DGln-Dab-Ser-
315



DThr-cOrn




Py Pp

P. putida

Asp-DOrn-DDab-Thr-Gly-DSer-Ser-Asp-
316

C2,3

Thr




Py G4R

P. putida

Asp-Orn-DAsp-Dab-Gly-Ser-cOrn
317



Py

P. putida

Asp-DOrn-DDab-Thr-Gly-DSer-DSer-Thr-
318

PpBTP16

Asp




Py

P. puida

DSer-DAla-DOrn-Gly-DAla-DAsp-c(DSer-
319

Pp39167

DThr)




iPy Pp

P. putida

Asp-Ala-Asp-DOrn-Ser-cOrn
320

BTP1






Py

P. tolaasii

DSer-Lys-Ser-DSer-Thr-DSer-Orn-Thr-
321

PT2192

DSer-Orn




Ps 7SR1
Pseudomonas spp.
DSer-DAsp-DThr-c(DSer-D-Orn-Ala-Gly-
322



DSer)




Ps A214
Pseudomonas spp.
DSer-DAla-Gly-DSer-DAla-DAsp-DThr-
323



DOrn




Azoverdin
Pseudomonas spp.
Hse-DHse-Dab-DOrn-DSer-Orn
324



A.macrocytogenes




PF-S024

Corynebacteria

SKRGRKRKDRRKKKANHGKRPNS
325


spp.





PF-001

S. epidermidis

MNNWIIVAQLSVTVINEIIDIMKEKQKG
326



M. luteus

GK




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jeikeium






PF-002

S. epidermidis

NDDAQ
327



P. mirabilis






C. albicans






C. jeikeium






C. jejuni






PF-003

S. epidermidis

MNNWIKVAQISVTVINEVIDIMKEKQN
328



M. luteus

GGK




P. mirabilis






C. albicans





MRSA





C. jeikeium






PF-004

S. epidermidis

ARLSKAIIIAVIVVYHLDVRGLF
329



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






PF-005

S. epidermidis

MESIFKIKLMNGICRSENMNMKKKNKG
330



E. coli

EKI



MRSA





S. pneumoniae






E. faecalis






PF-006

S. epidermidis

MGIIAGIIKFIKGLIEKFTGK
331



M. luteus






E. coli






P. aeruginosa





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-007

S. epidermidis

MGIIAGIIKVIKSLIEQFTGK
332



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-008

S. epidermidis

MIEIGSIAYLNGGSKKYNHILNQENR
333



M. luteus





MRSA





C. jejuni






PF-009

M. luteus

SKKYNHILNQENR
334



P. mirabilis






C. albicans






PF-010

S. epidermidis

MDIDVNKLLQAFVYFKSFEKLRHNNS
335



M. luteus






E. coli






C. albicans






PF-011

M. luteus

MFCYYKQHKGDNFSIEEVKNIIADNEM
336



E. coli

KVN




P. aeruginosa






S. pneumoniae






C. jeikeium






PF-012

S. epidermidis

WRGPNTEAGGKSANNIVQVGGAPT
337



M. luteus






P. mirabilis






E. coli






P. aeruginosa





MRSA





S. pneumoniae






C. jeikeium






C. jejuni






PF-013

M. luteus

LIQKGLNQTFIVVIRLNNFIKKS
338



P. mirabilis






E. coli






P. aeruginosa





MRSA





S. pneumoniae






C. jeikeium






C. jejuni






PF-014

E. coli

HPTDNKHN
339



C. jeikeium






PF-015

E. faecalis

SIDKRNLYNLKYYE
340



C. jeikeium






PF-016

S. epidermidis

RKQYDDLSFNFLY
341



E. faecalis






C. jeikeium






PF-017

E. coli

ESIIE
342



PF-018

E. coli

YYKTYFKEV
343



C. jeikeium






PF-020

S. epidermidis

MKIILLLFLIFGFIVVVTLKSEHQLTLFSI
344



M. luteus






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-021

S. epidermidis

FSLNFSKQKYVTVN
345



M. luteus






P. mirabilis






E. coli






C. albicans






E. faecalis






C. jeikeium






PF-022

M. luteus

MINELKNKNSGIMNNYVVTKESKL
346



P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-023

M. luteus

MTKNTIISLENEKTQINDSENESSDLRKA
347



C. jeikeium

K




PF-024

M. luteus

DLRKAK
348



C. albicans





MRSA





E. faecalis






C. jeikeium






PF-025

S. epidermidis

LLIIFRLWLELKWKNKK
349



M. luteus






P. mirabilis






E. coli






P. aeruginosa





MRSA





E. faecalis






C. jejuni






PF-026

S. epidermidis

SIHFIN
350



M. luteus






P. mirabilis






C. albicans





MRSA





E. faecalis






C. jeikeium






PF-027

M. luteus

HNARKYLEFISQKIDGDKLTKEDSL
351


MRSA





E. faecalis






C. jejuni






PF-028

S. epidermidis

ALDCSEQSVILWYETILDKIVGVIK
352



M. luteus





MRSA





PF-029

S. epidermidis

NSTNE
353



M. luteus






C. albicans






C. jejuni






PF-030

S. epidermidis

MTCHQAPTTTHQSNMA
354



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-031

M. luteus

MPHHSTTSSRIVVPAHQSNMASTPNLSI
355



C. albicans

TP




PF-033

S. epidermidis

MFIFKTTSKSHFHNNVKSLECIKIPINKN
356



M. luteus

R




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






PF-034

M. luteus

EPKKKHFPKMESASSEP
357



PF-035

S. epidermidis

SFYESY
358



M. luteus






E. coli






C. albicans





MRSA





C. jeikeium






C. jejuni






PF-036

S. epidermidis

ILNRLSRIVSNEVTSLIYSLK
359



M. luteus






P. mirabilis






E. coli






C. albicans





MRSA





S. pneumoniae






C. jejuni






PF-037

S. epidermidis

MTKKRRYDTTEFGLAHSMTAKITLHQA
360



M. luteus

LYK




P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-038

M. luteus

MAYKDEGKETKFAVKGYKD
361



PF-039

P. mirabilis

MLEEKNKSL
362



C. jeikeium






PF-040

S. epidermidis

MIHLTKQNTMEALHFIKQFYDMFFILNF
363



M. luteus

NV




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-041
MRSA
ELLVILPGFI
364



PF-042

S. epidermidis

LLLSYFRYTGALLQSLF
365



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-043

M. luteus

MIKNETAYQMNELLVIRSAYAK
366



C. jejuni






PF-044

S. epidermidis

KLKKYIHKPD
367



M. luteus





MRSA





C. jeikeium






PF-045

S. epidermidis

LDINDYRSTY
368



E. coli






E. faecalis






C. jejuni






PF-046

E. coli

LDFYLTKHLTLML
369



E. faecalis






C. jeikeium






PF-047

S. mutans

NQEPSLQQDKEQKDNKG
370



PF-048

S. epidermidis

LYFAFKKYQERVNQAPNIEY
371



M. luteus






E. coli





MRSA





C. jeikeium






C. jejuni






PF-049

S. epidermidis

AYYLKRREEKGK
372


MRSA





C. jeikeium






C. jejuni






PF-050

S. epidermidis

SYYLKRREEKGK
373



M. luteus






E. coli






C. jeikeium






PF-051

S. epidermidis

RFFNFEIKKSTKVDYVFAHVDLSDV
374



M. luteus






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-052

S. epidermidis

QELINEAVNLLVKSK
375



M. luteus






E. coli





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-053

S. epidermidis

KLFGQWGPELGSIYILPALIGSIILIAIVTL
376



M. luteus

ILRAMRK




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-054

S. epidermidis

VSISRFIGGGHVFNGNNKRNL
377



E. coli






PF-055

S. mutans

GHVFNGNNKRNL
378



PF-056

S. epidermidis

AEQLFGKQKQRGVDLFLNRLTIILSILFF
379



M. luteus

VLMICISYLGM




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-057

S. epidermidis

TMIVISIPRFEEYMKARHKKWM
380



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-058

S. epidermidis

FADQSQDNA
381



M. luteus






E. coli






C. albicans





MRSA





C. jeikeium






C. jejuni






PF-060

E. coli

HSSHL
382



C. albicans






C. jeikeium






PF-061

S. epidermidis

GYNSYKAVQDVKTHSEEQRVTAKK
383



S. pneumoniae






PF-062

S. epidermidis

MKKKRINNDILGRMIYSSSIDKRNLYNL
384



M. luteus

KYYE




E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-063

S. epidermidis

IAAIIVLVLFQKGLLQIFNWILIQLQ
385



M. luteus






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-064

E. coli

DYYGKE
386



PF-065

M. luteus

LEKNTRDNYFIHAIDRIYINTSKGLFPES
387



E. coli

ELVAWG




P. aeruginosa






C. albicans





MRSA





S. pneumoniae






C. jeikeium






C. jejuni






PF-066

M. luteus

IKGTVKAVDETTVVITVNGHGTELTFEK
388



E. coli

PAIKQVDPS




C. jeikeium






PF-067

S. epidermidis

DLIVKVHICFVVKTASGYCYLNKREAQ
389



M. luteus

AAI




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-068

S. epidermidis

SHLINNFGLSVINPSTPICLNFSPVFNLLT
390



M. luteus

VYGITCN




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-069

E. faecalis

FDPVPLKKDKSASKHSHKHNH
391



C. jejuni






PF-070

S. epidermidis

SMVKSEIVDLLNGEDNDD
392



C. jejuni






PF-071

S. epidermidis

HCVIGNVVDIANLLKRRAVYRDIADVIK
393



E. coli

MR




P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-073

S. epidermidis

CPSVTMDACALLQKFDFCNNISHFRHFF
394



M. luteus

AIKQPIER




P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-074

S. epidermidis

RDIHPIYFMTKD
395



M. luteus





MRSA





PF-075

M. luteus

FVNSLIMKDLSDNDMRFKYEYYNREKD
396



E. coli

T




P. aeruginosa





MRSA





C. jeikeium






PF-076

S. epidermidis

LYQYELLSKEEYLKCTLIINQRRNEQK
397



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-097

C. jeikeium

QPTQGEQGTRPRRPTPMRGLLI
398



PF-099

S. epidermidis

EIIAYLEGRFANA
399



M. luteus






E. coli






C. jeikeium






PF-101

S. mutans

DPVPERQEQACACHRTAKPGK
400



PF-104
MRSA
ERTAVNDLWI
401



C. jeikeium






PF-123

M. luteus

TTRPQVAEDRQLDDALKETFPASDPISP
402



E. coli






PF-124

S. epidermidis

MADGQIAAIAKLHGVPVATRNIRHFQSF
403



M. luteus

GVELINPWSG




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jejuni






PF-125

S. epidermidis

YVVGALVILAVAGLIYSMLRKA
404



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jejuni






PF-126

S. epidermidis

FSPEAFGIGAAGVLGSFVTGLLIGWVAS
405



M. luteus

LLRKAK




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-127

S. epidermidis

MLRYLSLFAVGLATGYAWGWIDGLAA
406



M. luteus

SLAV




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-128

M. luteus

GIKVVAARFEEIQFSENFDSIILA
407



P. aeruginosa






E. faecalis






PF-129

S. epidermidis

MKLLARDPWVCAWNDIW
408


MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-130

E. faecalis

LQRSDEESMPRRHEKYS
409



C. jeikeium






C. jejuni






PF-131

S. epidermidis

RRAAARTKGNRR
410



E. coli





MRSA





C. jeikeium






PF-132

S. epidermidis

RPGDGAAEQGRSR
411



C. jeikeium






PF-133

S. epidermidis

GDPTAGQKPVECP
412



C. jeikeium






C. jejuni






M. smegmatis






PF-134

S. epidermidis

GKANIKRQDCSAL
413



C. jeikeium






PF-135

S. epidermidis

PPARPARIPQTPTLHGASLFRQRS
414



M. luteus






E. coli






P. aeruginosa





MRSA





C. jeikeium






M. smegmatis






PF-136

S. epidermidis

LRGRVGRITACGYPP
415



M. luteus






P. mirabilis






E. coli





MRSA





E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-137

S. epidermidis

VLGKGHDLLDVGKTALKSRVFAWLGG
416



P. mirabilis

S




S. pneumoniae






C. jeikeium






C. jejuni






PF-138

S. epidermidis

AVHHSLLFR
417



M. luteus






P. mirabilis






E. coli






C. albicans





MRSA





C. jeikeium






C. jejuni






PF-139

S. epidermidis

ALSKPAIQARTLCRRQDPP
418



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-140

S. epidermidis

FHRRVIRASEWALTTRSFSTPLRSAAR
419



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-141

S. epidermidis

VVRRFQGM
420



M. luteus






C. albicans





MRSA





C. jeikeium






PF-142

S. mutans

GIDRGCQAAR
421



PF-143

S. epidermidis

LSPRPIIVSRRSRADNNNDWSR
422


MRSA





C. jeikeium






PF-144

S. epidermidis

RSGQPVGRPSRRAWLR
423



M. luteus






E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-145

S. epidermidis

GIVLTGRAGLVSGACSMALGVGLG
424



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-146

S. epidermidis

GCGKRRIITKSASRDTR
425



M. luteus






P. aeruginosa






C. albicans





MRSA





C. jeikeium






PF-147

S. epidermidis

RRPRRRRSGHGQSASAA
426



M. luteus





MRSA





PF-148

S. epidermidis

RRGCTERLRRMARRNAWDLYAEHFY
427



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-149

S. epidermidis

GKVSVLTRVPRSLGGAPANQ
428



M. luteus






E. coli





MRSA





C. jeikeium






PF-150

S. epidermidis

EIQAKGTG
429


MRSA





PF-151

S. epidermidis

EEYPARVPLSGEDVTEARRH
430


MRSA





E. faecalis






C. jeikeium






PF-152

S. epidermidis

VGYFIWKDSHSRKG
431



C. albicans





MRSA





E. faecalis






C. jeikeium






PF-153

M. luteus

GILARADCSQIA
432



P. mirabilis






E. coli





MRSA





PF-154

S. mutans

GIKKSKHPSTDDYVVKTTIDSL
433



PF-155

C. jeikeium

GRYGDDSKERQGRAQ
434



PF-156

S. epidermidis

LITAEQPATAPIAGK
435



C. jeikeium






PF-157

S. epidermidis

HTAVVWLAGVSGCVALSHCEPA
436



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-158

S. epidermidis

VRLESRPADLPE
437



PF-159

S. epidermidis

TMAFVEKAQLRVPVGDDLPV
438



PF-160

S. epidermidis

SFHASLTKNEKPIKSTG
439



PF-161

S. epidermidis

RGRALASTATTRPARRRR
440



M. luteus






E. coli






C. jejuni






PF-162

S. epidermidis

GIRRLHSVENLNREISHRMAGLR
441


MRSA





PF-163

S. epidermidis

TSWLRAAERQEIGEPTKTFGEKTTSL
442



PF-164

S. epidermidis

EEVSRALAGIGLGLGCRIG
443



M. luteus






E. coli






C. jeikeium






PF-165
MRSA
GPVSVVASLRRGTTVQRHSQNNHNKG
444



C. jejuni

KP




PF-166

E. coli

SKAVSRKRSI
445



C. jeikeium






PF-167

S. epidermidis

AIEGVIKKGACFKLLRHEMF
446



E. coli






C. albicans





MRSA





C. jeikeium






C. jejuni






PF-168

S. epidermidis

VLPFPAIPLSRRRACVAAPRPRSRQRAS
447



M. luteus






E. coli






C. albicans





MRSA





C. jeikeium






C. jejuni






PF-169

S. epidermidis

APGSAADSPRSRADD
448



E. coli






C. albicans






E. faecalis






C. jeikeium






PF-170

S. epidermidis

RLARGRPTNLCGRRG
449



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jejuni






PF-171

S. epidermidis

TQVTLCRTW
450



E. coli






P. aeruginosa






S. pneumoniae






PF-172

S. epidermidis

LTGVRRPWRAPWAGTSGWALR
451



M. luteus






E. coli






P. aeruginosa





MRSA





E. faecalis






C. jejuni






PF-173

S. epidermidis

AGRTAIVQGGG
452



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans






C. jeikeium






C. jejuni






PF-174

S. epidermidis

RGGDSPARRRPGLAGPGGPG
453



P. aeruginosa






C. jeikeium






PF-175

S. epidermidis

RRRPAGQRPEKASQAMIAA
454



E. faecalis






PF-176

S. epidermidis

RLTSNQFLTRITPFVFAQH
455



M. luteus






P. mirabilis






E. coli






C. albicans





MRSA





E. faecalis






C. jeikeium






PF-177

M. luteus

VTSEPGIAHDIRLLPRAAAFR
456


MRSA





E. faecalis






C. jeikeium






PF-178

S. epidermidis

EVYSSPTNNVAITVQNN
457



M. luteus






B. subtilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-180

S. epidermidis

SGLGDLGFSSEAK
458



M. luteus






P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jejuni






M. smegmatis






PF-181

S. epidermidis

GIAPRRNEWGAVGGR
459



M. luteus






E. coli





MRSA





E. faecalis






C. jeikeium






PF-182

S. epidermidis

LPATRDKTRVPASVAGAP
460



M. luteus






E. coli






E. faecalis






C. jeikeium






PF-183

S. epidermidis

KPGISVENRQ
461



M. luteus






E. coli






C. albicans





MRSA





E. faecalis






C. jeikeium






PF-184

S. epidermidis

LIADRHIRA
462



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





C. jeikeium






PF-185

E. coli

RPAQARQGPGGLIADRHIRA
463



P. aeruginosa






PF-186

S. epidermidis

DADKNLSLERDRFAWRVAAP
464



M. luteus






E. coli






P. aeruginosa





MRSA





C. jeikeium






PF-187

S. epidermidis

EIQKIAKGVSGQVYGPSRQITISKKR
465



M. luteus






E. coli





MRSA





PF-188

S. epidermidis

ARTFAGRLGTRYFGGLMRSTKA
466



M. luteus






E. coli






C. albicans





MRSA





E. faecalis






PF-189

S. epidermidis

GNLTRSREAARATQ
467



M. luteus






C. albicans





MRSA





E. faecalis






C. jejuni






PF-190

S. epidermidis

HFILRKPLLFMIHSLKTGPLDRF
468



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-191

E. coli

QFCNFAWLFLASNNAQVSALA
469



P. aeruginosa






C. jejuni






PF-192

S. epidermidis

VEEDEAPPPHY
470



M. luteus






P. aeruginosa






C. albicans






E. faecalis






C. jeikeium






PF-193

S. epidermidis

PPHCPPGHAKKGWC
471



M. luteus






E. coli





MRSA





E. faecalis






C. jejuni






PF-194

C. jeikeium

MKGNKLATAHEQPVKNSAPPL
472



PF-195

S. epidermidis

EMAEGSADDRLRKTPRDC
473



M. luteus






E. faecalis






C. jeikeium






PF-196

S. epidermidis

TTARYIRRQCHTSITPLSQG
474



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jejuni






PF-197

S. epidermidis

CNALLRRGHPPSAL
475



M. luteus






C. albicans






E. faecalis






C. jejuni






PF-200

S. epidermidis

GIELKSLIMAQIERWRQA
476



M. luteus





MRSA





E. faecalis






C. jeikeium






PF-201

S. epidermidis

GCRPASLSDADPDGR
477



M. luteus






E. coli






C. albicans






E. faecalis






C. jeikeium






C. jejuni






PF-202

S. epidermidis

ALNRASLRLALGE
478



M. luteus






E. coli





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-203

S. epidermidis

SWKCHHLAI
479



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jejuni






PF-204

S. epidermidis

ALQKQDMNLPSVKNQLVFLKSTG
480



P. mirabilis






E. coli






P. aeruginosa






C. albicans






C. jejuni






PF-205

S. epidermidis

AGVLETPRCRGEYGAN
481



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-206

M. luteus

KLRSASKKSLQEKSCGIMPEKPAG
482



C. albicans






C. jeikeium






C. jejuni






PF-207

M. luteus

AAGCRDLGSLSSLVTNPS
483



C. jeikeium






PF-208

S. epidermidis

DAYHCHLVRSPDAHDLSMRIGFV
484



C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-209

C. albicans

NYAVVSHT
485



C. jeikeium






C. jejuni






PF-210

S. epidermidis

EREDGCDAMPLP
486



P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-211

S. epidermidis

DSFDSLSPFRERGGEREDGCDAMPLP
487



M. luteus






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-212

M. luteus

NDSKASN
488



P. aeruginosa






PF-213

S. epidermidis

MTTGVDFIIEKV
489



PF-214

S. mutans

GHLRVCWVFSASLLTPFRSATLI
490



S. epidermidis






M. luteus






E. coli






P. aeruginosa






A. baumannii






PF-215

S. epidermidis

ELKITNYNVNTVLYRYYKWGNDLCE
491



M. luteus






P. aeruginosa






A. baumannii






PF-216

S. mutans

ESVDKITEALEEDGFPAKVQ
492



E. coli






PF-217

S. mutans

DWEFTHKTIPQKK
493



PF-218

S. epidermidis

SETPEKPVGTFFYSIYYKIIL
494



M. luteus






P. aeruginosa






A. baumannii






PF-219

S. epidermidis

FLALAVIAGLFKVILIYAAPYLK
495



M. luteus






P. aeruginosa






A. baumannii






PF-221

S. epidermidis

VFDNIDINF
496



M. luteus






P. aeruginosa






PF-222

S. epidermidis

HIKETR
497



PF-223

S. epidermidis

VKFCIECQTKLERKRR
498



M. luteus






A. baumannii






PF-224

S. epidermidis

DYFYITLSQKNTF
499



P. aeruginosa






A. baumannii






PF-225

S. epidermidis

MNCASPEFKKLMELYK
500



PF-226

A. baumannii

LMFFSENMDKRDTLSGKFRYFAGSKVI
501



KLMNWLSENGK




PF-228

S. mutans

NQLGSQAFAQL
502



PF-229

S. epidermidis

DPILIQIGFTRFALRKAEAEKIEIQVEEGV
503



M. luteus

PA




P. aeruginosa






A. baumannii






PF-230

S. mutans

EDKPTNTIQEIKPVKWQ
504



PF-231

S. mutans

AVRDFKKSVREEDEAASLNSPRTIDAQ
505



VKTSESTSVKS




PF-232

S. epidermidis

FDQLYALEREGKLDELLA
506



M. luteus






PF-233

S. epidermidis

DANAMARTTIAIVYILALIALTISYSL
507



M. luteus






P. aeruginosa






A. baumannii






PF-234

S. epidermidis

RTPYILRS
508



M. luteus






PF-235

S. epidermidis

GIPFSKPHKRQVNYMKSDVLAYIEQNK
509



M. luteus

MAHTA




PF-236

S. mutans

KEIRTATVAELNAKRRLTSAEQALAEVS
510



S. epidermidis






E. coli






C. albicans






S. pneumoniae






E. faecalis






PF-237

S. epidermidis

YVKPKVGVHE
511



PF-238

S. mutans

RNAVVVTEATFPKYEEEITNYLNRRFGE
512



S. epidermidis

DWSLKLEKCSVA




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-239

S. mutans

PKHNVVTGVSVDLDYKP
513



E. coli






PF-240

S. mutans

RITEVPPDEHSDR
514



E. coli






PF-242

S. mutans

KLFEDPLIKSKAVENFQTTWHEQCLAK
515



E. coli

ELAKNM




PF-244

S. epidermidis

HMRTISYLLAFAKFSLFIPPKQSLKRL
516



M. luteus






P. aeruginosa






A. baumannii






PF-245

S. epidermidis

MNDVKPVVQPKQTLKAFLVQLLSVRA
517



M. luteus

GVYIKQNNQLPKTKG




P. aeruginosa






A. baumannii






PF-246

S. mutans

QPDEKAEFFDPSLDKVYRHPTFYHIPDG
518



IEHM




PF-247

S. epidermidis

ETAASETH
519



PF-248

S. mutans

ILSKLWFWMINSLGVVLLVSYWLLAK
520



S. epidermidis

WGVA




M. luteus






E. coli






P. aeruginosa






A. baumannii






PF-249

S. epidermidis

INSRYKISF
521



M. luteus






PF-252

S. mutans

MKKLVAALAVIVILTGCVYDPVNYDKI
522



HDQEFQDHLRQNG




PF-253

S. epidermidis

VRDDDS
523



M. luteus






PF-254

S. epidermidis

FIYGVGFVPHFWLWKWLFSPWIAWPL
524



M. luteus

MLLGYYIWFLT




P. aeruginosa






A. baumannii






PF-255

P. aeruginosa

DHKINESQHNPFRSDSNKQNVDFF
525



PF-256

S. epidermidis

EYFKQVYVKNEKIYSFWICKDLSPKEA
526



AKRAEDILVKLK




PF-257

S. epidermidis

VWENRKKYLENEIERHNVFLKLGQEVI
527



KGLNALASRGR




PF-259

S. epidermidis

LPFSKIGRRVSYKKKDVLKYEQSKTVL
528



P. aeruginosa

NTAQLATV




A. baumannii






PF-262

S. mutans

DPHSEIDVTRYCQLHHFTCQTMQISERE
529



S. epidermidis

FHYLIETQ




M. luteus






E. coli






P. aeruginosa






A. baumannii






PF-263

S. epidermidis

NLKKCPC
530



M. luteus






A. baumannii






PF-265

S. epidermidis

MKTLFFPLFLIIFVLIIQALDQSYQKKIGI
531



M. luteus

SKPQKHPEFMQ




A. baumannii






PF-266

S. mutans

DQEKKNKTEESTEQ
532



PF-267

M. luteus

SDDKRTD
533



PF-268

S. mutans

EVLLSDLRPDIFSET534




PF-270

S. epidermidis

MYLTPYAWIAVGSIFAFSVTTIKIGDQN
535



M. luteus

DEKQKSHKNDVHKR




P. aeruginosa






PF-271

S. epidermidis

AAQPQTTSP
536



M. luteus






P. aeruginosa






A. baumannii






PF-273

S. epidermidis

LVGALLIFVALIYMVLKGNADKN
537



M. luteus






P. aeruginosa






A. baumannii






PF-275

S. mutans

LVSGVANTVKNTAHTVGNTAKHAGHV
538



AADTTVKATKKQQVK




PF-276

S. epidermidis

LDLALSTNSLNLEGFSF
539



PF-278

M. luteus

LSLATFAKIFMTRSNWSLKRFNRL
540



A. baumannii






PF-279

S. mutans

SHIGFISISACLAVLLGIARLFVWTWVKF
541



S. epidermidis

FA




M. luteus






E. coli






P. aeruginosa






A. baumannii






PF-281

S. mutans

SYNTYYNKLIHGQRTPDGM
542



E. coli






PF-282

S. mutans

QNNDTSAWCGSAHKNGNS
543



PF-283

B. subtilis

MIRIRSPTKKKLNRNSISDWKSNTSGRF
544



B. fragilis

FY




C. difficile






PF-284

C. difficile

MRYITYSLIPRLLSKKVIHQQ
545



PF-285

S. mutans

VPAKLLRVIDEIPE
546



PF-288

S. mutans

IYQLLNIEYSEDD
547



E. coli






PF-289

C. difficile

MGRHLWNPSYFVATVSENTEEQIRKYR
548



KNK




PF-291

S. mutans

DVDGAIESEL
549



E. coli






PF-292

S. epidermidis

SFVSTTVRLIFEESKRYKF
550



B. subtilis






B. fragilis






PF-294

S. epidermidis

DFLVNFLWFKGELNWGKKRYK
551



C. difficile






PF-295

C. difficile

NIQVYESECGNYIFKKSDESFLIDIFDKN
552



GTH




PF-297

S. epidermidis

ISKGIDDIVYVINKILSIGNIFKIIKRK
553



B. subtilis






B. fragilis






PF-299

B. subtilis

LATKLKYEKEHKKM
554



PF-300

B. subtilis

VKDVLLELFNKIIGA
555



C. difficile






PF-301

C. difficile

GIVLIGLKLIPLLANVLN
556



PF-304

S. mutans

LVKDTSDIKNDLNNIEIVTSKNSNDIAKL
557



KSVK




PF-305

C. difficile

MREWICPSCNETHDRDINASINILKEGL
558



RLITIQNK




PF-306

C. difficile

GCILPHKKDNYNYIMSKFQDLVKITSKK
559



PF-307

S. epidermidis

MKRRRCNWCGKLFYLEEKSKEAYCCK
560



B. subtilis

ECRKKAKKVKK




B. fragilis






C. difficile






PF-308

C. difficile

QQYLILDRM
561



PF-309

S. mutans

GIPGMTAAPAEENEQEENADEE
562



E. coli






PF-311

C. difficile

IDAVTKKKTTCMIRAPTKIPIAHTDN
563



PF-313

S. epidermidis

YITSHKNARAIIKKFERDEILEEVITHYL
564



C. difficile

NRK




PF-314

S. mutans

ECLKKAIKSKALNKAFKIDVPDEVYDN
565



LLMELEEYEK




PF-317

S. mutans

LILVSDI
566



PF-319

S. epidermidis

SIGSMIGMYSFREIKTKHIKFTFGIPFILFL
567



B. subtilis

QFLLVYFYILK




C. difficile






PF-320

S. mutans

DSGYYALLENKEERVVWDGEVVANNI
568



E. coli

FNNLWIVVNKVKTG




PF-323

S. mutans

ARESIEKSHVPVDATIVGVVDSFEVFDE
569



PF-324

C. dffficile

HFSLL
570



PF-325

S. mutans

LTIDEKLRNHR
571



E. coli






PF-326

S. mutans

VIVGNLGAQKEKRNDTPISAKKDIIVIGD
572



E. coli

KTVRVRADLHH




PF-328

S. mutans

NGNEKAFSEVENLVK
573



PF-329

S. epidermidis

IGILFDKSVRKY
574



PF-333

S. mutans

YMTKKLVEMAEQQMAGKSNR
575



PF-334

S. epidermidis

QQYLILDRM
576



C. dffficile






PF-336

S. mutans

MLTSRKKRLKKIVEEQNKKDESI
577



E. coli






PF-337

S. epidermidis

YMTKKLVEMAERQMAGK
578



PF-338

S. mutans

KGTSCPDQLSKAIRQSI
579



PF-340

S. mutans

VKDVLLELFNKIIGA
580



E. coli






PF-344

B. subtilis

DERLPEAKAIRNFNGSVMVLGR
581



C. jejuni






PF-347

S. epidermidis

GIFTGVTVVVSLKHC
582



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-348

B. subtilis

ESASAAEWYNPNMNVKKAICMG
583



E. coli






P. aeruginosa






C. albicans






E. faecalis






C. jejuni






PF-349

S. epidermidis

MPKSCHVPVLCDFFFLVIIKFLALFKTIQ
584



B. subtilis

S




B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-350

S. epidermidis

LAVILRAIVY
585



E. coli






E. faecalis






C. jeikeium






C. jejuni






PF-351

S. mutans

YLFFKGKKVAEEEATKDEVKR
586



PF-352

C. jeikeium

RVKKIG
587



PF-353

S. epidermidis

EKTNFKGVKRNFYKKASFFV
588



M. luteus






B. subtilis






E. coli






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-354

S. epidermidis

FTFSKCRASNGRGFGTLWL
589



B. subtilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-355

S. epidermidis

WIAIGLLLYFSLKNQ
590



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-356

S. epidermidis

VSIKIGAIVIGMIGLMELLTE
591



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-357

S. epidermidis

MLTIIIGFIFWTMTLMLGYLIGEREGRK
592



M. luteus

RE




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-358

S. epidermidis

RNTAHNIKWRSKN
593



B. subtilis






E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-359

S. epidermidis

MTVMEDPGSEQRNKIQSPMKGEDFSAL
594



B. fragilis

FGR




P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jeikeium






PF-360

S. epidermidis

MEQKVKVIFVPRSKPDNQLKTFVSAVL
595



B. subtilis

FKA




E. coli






P. aeruginosa






C. albicans






E. faecalis






C. jeikeium






C. jejuni






PF-361

S. epidermidis

NQVTEGIRLLVE
596



E. coli






E. faecalis






C. jejuni






PF-362

S. epidermidis

NIERILKEKVWMIRCVE
597



E. coli






P. aeruginosa






C. albicans






E. faecalis






C. jejuni






PF-363

B. subtilis

SMLSVTVMCLMHASVAANQAMEKKV
598



E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






PF-364

S. epidermidis

LVNGIKI
599



B. fragilis






P. aeruginosa






C. jeikeium






C. jejuni






PF-365

S. epidermidis

LYKQKIQLEEELEKLKDDRQ
600



B. subtilis






B. fragilis






P. aeruginosa






C. albicans






PF-366

S. epidermidis

ALCSVIKAIELGIINVHLQ
601



M. luteus






B. fragilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-367

B. subtilis

TKTPGTFTPGTGIQKTAVPL
602



PF-368

C. jeikeium

MLKQTA
603



C. jejuni






PF-369

B. subtilis

MSEAVNLLRGARYSQRYAKNQVPYEVI
604



B. fragilis

IEK




E. coli






P. aeruginosa






C. albicans






S. pneumoniae






C. jeikeium






C. jejuni






PF-370

S. epidermidis

VIFLHKESGNLKEIFY
605



E. coli






P. aeruginosa






E. faecalis






C. jejuni






PF-371

S. epidermidis

TFIYNEF
606



B. fragilis






C. jejuni






PF-372

C. jeikeium

KKQDKRIEDKYKRMKKGD
607



C. jejuni






PF-373

S. epidermidis

HFYLLFER
608



E. coli






P. aeruginosa






C. albicans





MRSA





E. faecalis






C. jejuni






PF-374

S. epidermidis

HLFFVKGMFILCQKNQINDE
609



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-375

S. epidermidis

MDSAKAQTMRTDWLAVSCLVASAYLR
610



B. subtilis

SMLA




B. fragilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-376

S. epidermidis

MTVFEALMLAIAFATLIVKISNKNDKK
611



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-378

B. subtilis

ESAKSNLNFLMQEEWALFLLL
612



B. fragilis






E. coli






P. aeruginosa






C. jeikeium






PF-379

S. epidermidis

VFVVLFIIYLASKLLTKLFPIKK
613



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-380

S. epidermidis

KKIIPLITLFVVTLVG
614



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-381

E. coli

QGANPCQQVGFTVNDPDCRLAKTV
615



P. aeruginosa






C. jejuni






PF-382

S. epidermidis

KYKCSWCKRVYTLRKDHKTAR
616



B. subtilis






B. fragilis






E. coli






P. aeruginosa






E. faecalis






C. jeikeium






C. jejuni






PF-383

S. epidermidis

WSEIEINTKQSN
617



B. subtilis






B. fragilis






E. coli






C. jejuni






PF-384

E. faecalis

HISKERFEAY
618



C. jeikeium






C. jejuni






PF-385

S. epidermidis

MIKKSILKIKYYVPVLISLTLILSA
619



E. coli






P. aeruginosa






C. albicans






E. faecalis






PF-386

S. epidermidis

FTLTLITTIVAILNYKDKKK
620



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-387

B. subtilis

GAVGIAFFAGNMKQDKRIADRQNKKSE
621



E. coli

KK




P. aeruginosa






E. faecalis






C. jeikeium






C. jejuni






PF-388

E. faecalis

ITPLLDEIGKVCIDKISK
622



C. jeikeium






C. jejuni




PF-389

S. epidermidis

GLQFKEIAEEFHITTTALQQWHKDNGY
623





C. albicans

PIYNKNNRK



MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-390

S. epidermidis

VVAYVITQVGAIRF
624



P. aeruginosa






C. albicans





MRSA





PF-392

S. epidermidis

DPAGCNDIVRKYCK
625



B. subtilis






S. pneumoniae






C. jeikeium






C. jejuni






PF-393

S. epidermidis

DLVQSILSEFKKSG
626



E. coli






C. albicans





MRSA





S. pneumoniae






C. jejuni






PF-394

S. epidermidis

VLKEECYQKN
627


MRSA





C. jejuni






PF-395

S. epidermidis

YCVPLGNMGNMNNKIW
628



E. coli






P. aeruginosa






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-396

S. epidermidis

LIYTILASLGVLTVLQAILGREPKAVKA
629



E. coli






P. aeruginosa






C. albicans






E. faecalis






C. jeikeium






PF-397

S. epidermidis

VEDLMEDLNA
630


MRSA





S. pneumoniae






E. faecalis






C. jejuni






PF-398

S. epidermidis

ILVVLAGILLVVLSYVGISKFKMNC
631



B. subtilis






B. fragilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-399

S. epidermidis

FPIISALLGAIICIAIYSFIVNRKA
632



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jejuni






PF-400

S. epidermidis

VIAWKFRNKFENSGV
633



E. coli






S. pneumoniae






E. faecalis






C. jeikeium






PF-401

S. epidermidis

YWLSRVTTGHSFAFEKPVPLSLTIK
634



E. coli






P. aeruginosa





MRSA





E. faecalis






C. jejuni






PF-402

S. epidermidis

FIDVLKSKINEFLN
635



P. aeruginosa






E. faecalis






C. jejuni






PF-403

E. coli

LLSTEQLLKYYDGETFDGFQLPSNE
636



P. aeruginosa






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-404

S. epidermidis

VLYFQATVV
637



E. coli






P. aeruginosa






E. faecalis






C. jeikeium






C. jejuni






PF-405

S. epidermidis

LVRIEVDDLEEWYERNFI
638



E. coli






E. faecalis






PF-406

E. coli

YLEMNADYLSNMDIFDELWEKYLENN
639



C. jejuni

K




PF-407

S. epidermidis

KPKNKKEKTVISYEKLLSMY
640



B. subtilis






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-408

S. epidermidis

YCVPLGNMGNMNNKIW
641



E. coli






P. aeruginosa





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-409

S. epidermidis

DLVQSILSEFKKSG
642


MRSA





C. jeikeium






C. jejuni






PF-410

S. epidermidis

FALELIALCRNLFIVYFP
643



M. luteus






B. fragilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans






MRSA






S. pneumoniae






E. faecalis






PF-411

M. luteus

WVAVAILLNIALQTQLT
644



B. subtilis






B. fragilis






P. mirabilis






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-412

M. luteus

TSGWLGQLEQ
645



E. coli






C. albicans






C. jeikeium






C. jejuni






PF-413

P. aeruginosa

TFAGSIKIGVPDLVHVTFNCKR
646



C. albicans






C. jejuni






PF-414

E. coli

LLNKKLE
647



C. albicans






C. jeikeium






PF-416

S. pneumoniae

SKAGLYGKIERSDKRE
648



C. jeikeium






PF-417

S. epidermidis

DSYFRS
649



C. jeikeium






C. jejuni






PF-418

S. epidermidis

FFLVHFYIRKRKGKVSIFLNYF
650



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-421

C. jeikeium

KHCFEITDKTDVV
651



PF-422

C. albicans

MSRKKYENDEKSQKKLKIGRKSDVFYG
652


MRSA
IID




C. jeikeium






PF-423

S. epidermidis

AGKKERLLSFREQFLNKNKKK
653



M. luteus






E. coli






S. pneumoniae






E. faecalis






C. jeikeium






PF-424

S. epidermidis

IAAFVTSRAFSDTVSPI
654



C. albicans





MRSA





PF-425

S. epidermidis

MMELVLKTIIGPIVVGVVLRIVDKWLN
655



M. luteus

KDK




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-426

S. epidermidis

MLQKYTQMISVTKCIITKNKKTQENVD
656



E. coli

AYN




P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-427

M. luteus

YVLEYHGLRATQDVDAFMAL
657



P. aeruginosa






C. albicans






C. jejuni






PF-428

S. epidermidis

ENEESIF
658



C. albicans






E. faecalis






C. jeikeium






PF-429

S. epidermidis

AATLICVGSGIMSSL
659



S. pneumoniae






C. jeikeium






PF-430

S. epidermidis

AVVCGYLAYTATS
660



M. luteus






E. coli






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-431

S. epidermidis

VAYAAICWW
661



M. luteus






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-432

S. epidermidis

FNGDSEFFLCIAF
662



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-433

S. epidermidis

MRKEFHNVLSSGQLLADKRPARDYNR
663



E. coli

K




S. pneumoniae






C. jeikeium






PF-434

S. epidermidis

GQLLADKRPARDYNRK
664



M. luteus






S. pneumoniae






C. jeikeium






PF-435

C. jeikeium

MSRWDGHSDKGEAPAGKPPMHGFGLN
665



GENK




PF-436

C. jeikeium

KKHVLVGKQEKNG
666



PF-438

S. epidermidis

QPYFQNQFKKITGYTPLQYRKEKR
667



E. coli






S. pneumoniae






C. jeikeium






C. jejuni






PF-439

S. epidermidis

RVLVLKKFHGIMDGNRNVAVFFVGQ
668



M. luteus






B. fragilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-440

S. epidermidis

MFIISPDLFNIAVILYILFFIHDILLLILS
669



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-441

C. jeikeium

TQVHKMARGIDPGPANGIYR
670



PF-442

S. epidermidis

MQIFYIKTKIFLSFFLFLLIFSQCFYKIEE
671



E. coli






C. albicans






S. pneumoniae






E. faecalis






PF-443

S. epidermidis

KLLYFFNYFENLQQVHLLVQL
672



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-444

M. luteus

MAAKLWEEGKMVYASSASMTKRLKL
673



C. albicans

AMSKV




S. pneumoniae






C. jeikeium






PF-445

M. luteus

ASMTKRLKLAMSKV
674



S. pneumoniae






C. jeikeium






PF-446

M. luteus

SGNEKV
675



C. jeikeium






PF-447

S. epidermidis

IDKSRNKDQFSHIFGLYNICSG
676



M. luteus






E. coli






S. pneumoniae






PF-448

S. epidermidis

SLQSQLGPCLHDQRH
677



M. luteus






P. mirabilis






E. coli






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-450

S. epidermidis

HRNLIILQRTIFI
678



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-451

S. epidermidis

MVNYIIGSYMLYREQNNNEALRKFDIT
679



M. luteus

LAM




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-452

M. luteus

MNNWIKVAQISVTVINEVIDIMKEKQN
680



P. aeruginosa

GGK




C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






M. smegmatis






PF-453

M. luteus

IIQDIAHAFGY
681



E. coli






P. aeruginosa






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-454

S. epidermidis

MSVFVPVTNIFMFIMSPIFNVNLLHFKV
682



M. luteus

YI




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-456

C. albicans

TCVKPRTIN
683


MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-457

C. albicans

INKYHHIA
684



S. pneumoniae






E. faecalis






C. jeikeium






PF-458

S. epidermidis

ISLIIFIMLFVVALFKCITNYKHQS
685



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-459

P. aeruginosa

EKRMSFNENQSHRPLL
686



PF-460

S. epidermidis

MEHVLPFQNTPPNIVIIYKDFTHLKSITF
687



M. luteus

S




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-461

E. coli

MTLAIKNCSVTKCLGFGDFVNDDSDSY
688



S. pneumoniae

FDA




PF-462

E. faecalis

KNKTDTL
689



C. jeikeium






PF-463

S. epidermidis

MVILVFSLIFIFTDNYLVYQSKSIKEDVM
690



E. coli

I




P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






M. smegmatis






PF-464

S. epidermidis

VDMVNRFLGN
691



C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-465

S. epidermidis

KPVGKALEEIADGKIEPVVPKEYLG
692



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-466
MRSA
VRKSDQ
693



C. jeikeium






C. jejuni






PF-467
MRSA
YYKDYFKEI
694



E. faecalis






C. jeikeium






C. jejuni






PF-469

S. epidermidis

YKVNYNNIDNHFNTLRH
695



M. luteus






P. mirabilis






E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-470

M. luteus

PYSDSYATRPHWEQHRAR
696



E. coli





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-471

S. epidermidis

MVGKIRGVTPRNDLLNANITGQLNLNY
697



M. luteus

RLI




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-472

S. epidermidis

MHISHLLDEVEQTEREKAVNVLENMNG
698



E. coli

NVI




P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-473

S. epidermidis

MAADIISTIGDLVKWIIDTVNKFKK
699



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-474

S. epidermidis

MHRNLVLVKMEPIPHIMIIANQIGIIIEKA
700



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-475

S. epidermidis

MREKVRFTQAFKLFWTNYFNFKGRSRR
701



M. luteus

SEY




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-476

M .luteus

WADAQYKLCENCSE
702



P. mirabilis






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-477

S. epidermidis

HKNKLNIPHIKS
703



M. luteus






C. albicans






S. pneumoniae






C. jeikeium






C. jejuni






PF-478

S. epidermidis

HLFILKSHLKPFPPFRYTYD
704



M. luteus






P. mirabilis






E. coli






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF -479

S. epidermidis

AYILKRREEKNK
705



M. luteus






P. mirabilis






E. coli






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-480

S. epidermidis

MVEILVNTAISVYIVALYTQWLSTRDNL
706



M. luteus

KA




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-481

C. jeikeium

DELYEIMDKVIEEFNKDIEQNNNNGNN
707



EDLTENKIN




PF-482

S. epidermidis

LVGYVRTSGTVRSYKIN
708



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-483

P. mirabilis

EDNKDKKDKKDK
709



C. jeikeium






C. jejuni






PF-484

S. epidermidis

HKKDIRKQVFKN
710



M. luteus






P. mirabilis






E. coli






E. faecalis






C. jeikeium






C. jejuni






PF-486

S. mutans

MQKEGEEDY
711



PF-487

S. mutans

MYKAIAVLAMTIMAFFIFVYPFFIVGLIL
712



E. coli

G




PF-488

S. mutans

YPNEQGHHKNNLKNIIIE
713



E. coli






PF-489

S. mutans

KVDRVSTTITEKIK
714



PF-490

S. mutans

RLILVSGNATVQK
715



E. coli






PF-491

S. mutans

IHQYSSKPDIVGQEAKTVQQINS
716



E. coli






PF-492

S. mutans

IQIDAASFYSISKSTIK
717



B. subtilis






E. coli






PF-493

S. mutans

PGAFFFCRGRGCWCGIGW
718



B. subtilis






E. coli






PF-494

S. mutans

FTEPLRPLQAKGQIISIKPSTSSS
719



PF-495

S. mutans

KGIYKKRTY
720



E. coli






PF-496

S. mutans

EVTKRLVALAQQQLRG
721



E. coli






PF-497

S. mutans

LVLRICTDLFTFIKWTIKQRKS
722



B. subtilis






E. coli






PF-498

S. mutans

MSEEEEVSEKVYNYLRRNEFFEVRKEE
723



E. coli

FSA




PF-499

S. mutans

VYSFLYVLVIVRKLLSMKKRIERL
724



E. coli






PF-500

S. mutans

MGIFKEEKIKFIDCKGEEVILKIKIKDIKK
725



E. coli






PF-501

S. mutans

GSTAHKSPIGSTNNQWGMKKTPTD
726



PF-502

S. mutans

NKGKQMQDQTGKQPIVDNG
727



PF-503

S. mutans

VVTLKDIVAVIEDQGYDVQ
728



PF-504

S. mutans

ILSVELSTKTSASGS
729



E. coli






PF-505

S. mutans

GYTKDPGTGI
730



PF-506

S. mutans

SGRGFALIVVLFILLIIVGAACIR
731



E. coli






PF-507

S. mutans

LALSIANLFKKKA
732



E. coli






PF-508

S. mutans

VSTFGKVVKVVDEK
733



PF-509

S. mutans

EAKVQAKGEQIACNNY
734



B. subtilis






E. coli






PF-510

S. mutans

WYLYKKQSNQNDRGIPK
735



E. coli






PF-511

E. coli

VMQSLYVKPPLILVTKLAQQN
736



P. aeruginosa






S. pneumoniae






C. jeikeium






PF-512

S. pneumoniae

SFMPEIQKNTIPTQMK
737



C. jeikeium






PF-513

C. albicans

SNGVGLGVGIGSGIRF-NH2
738



PF-514

S. epidermidis

QRFYKLFYHIDLTNEQALKLFQVK
739



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-515

S. epidermidis

DKSTQDKDIKQAKLLAQELGL-NH2
740



C. albicans






S. pneumoniae






C. jeikeium






PF-517

C. jejuni

VKPTMTASLISTVC
741



PF-518

S. epidermidis

SFYSKYSRYIDNLAGAIFLFF
742



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-519

M. luteus

YLVYSGVLATAAAF-NH2
743



E. faecalis






C. jeikeium






PF-520

S. epidermidis

LGLTAGVAYAAQPTNQPTNQPTNQPTN
744



M. luteus

QPTNQPTNQPRW-NH2




E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-521

S. epidermidis

CGKLLEQKNFFLKTR
745



E. coli






P. aeruginosa






S. pneumoniae






E. faecalis






PF-522

S. epidermidis

FELVDWLETNLGKILKSKSA-NH2
746



E. coli






P. aeruginosa






S. pneumoniae






E. faecalis






PF-523

S. epidermidis

ASKQASKQASKQASKQASKQASRSLKN
747



M. luteus

HLL




C. albicans






S. pneumoniae






C. jeikeium






C. jejuni






PF-524

S. epidermidis

PDAPRTCYHKPILAALSRIVVTDR
748



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-526

S. epidermidis

VLLLFIFQPFQKQLL-NH2
749



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-527

S. epidermidis

GSVIKKRRKRMAKKKHRKLLKKTRIQR
750



M. luteus

RRAGK




P. mirabilis






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-528

S. epidermidis

LVDVVVLIRRHLPKSCS-NH2
751



P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-529

S. epidermidis

LSEMERRRLRKRA-NH2
752



E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-537

S. epidermidis

LANDYYKKTKKSW
753



M. luteus






P. mirabilis






E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-539

S. epidermidis

SIILTKKKRRKIPLSIDSQIYKYTFKQ
754


M. luteus





B. subtilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-540

C. albicans

KSILILIKVIFIGQTTIIL
755



PF-542

C. jeikeium

KKDNPSLNDQDKNAVLNLLALAK
756



PF-543

S. epidermidis

NILFGIIGFVVAMTAAVIVTAISIAK
757



M. luteus






B. subtilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-544

S. epidermidis

FGEKQMRSWWKVHWFHP
758



M. luteus






P. mirabilis






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-545

S. epidermidis

RESKLIAMADMIRRRI-NH2
759



E. coli






P. aeruginosa






S. pneumoniae






E. faecalis






C. jeikeium






PF-546

S. epidermidis

PIIAPTIKTQIQ
760



E. coli






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






PF-547

S. epidermidis

WSRVPGHSDTGWKVWHRW-NH2
761



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-548

M. luteus

ARPIADLIHFNSTTVTASGDVYYGPG
762



P. mirabilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-549

E. coli

TGIGPIARPIEHGLDS
763



C. albicans






S. pneumoniae






C. jeikeium






PF-550

S. pneumoniae

STENGWQEFESYADVGVDPRRYVPL
764



PF-551

S. pneumoniae

QVKEKRREIELQFRDAEKKLEASVQAE
765



PF-552

S. pneumoniae

ELDKADAALGPAKNLAPLDVINRS
766



PF-553

S. epidermidis

LTIVGNALQQKNQKLLLNQKKITSLG
767



E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-554

S. pneumoniae

AKNFLTRTAEEIGEQAVREGNINGP
768



PF-555
MRSA
EAYMRFLDREMEGLTAAYNVKLFTEAI
769



S. pneumoniae

S




C. jeikeium






PF-556

S. epidermidis

SLQIRMNTLTAAKASIEAA
770



M. luteus






B. fragilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-557

S. pneumoniae

AANKAREQAAAEAKRKAEEQAR
771



PF-558

S. epidermidis

ADAPPPLIVRYS
772



E. coli






C. albicans






C. jeikeium






C. jejuni






PF-559

S. epidermidis

SRPGKPGGVSIDVSRDRQDILSNYP
773



M. luteus






C. albicans






C. jeikeium






C. jejuni






PF-560

S. epidermidis

FGNPFRGFTLAMEADFKKRK
774



M. luteus






E. coli






S. pneumoniae






C. jeikeium






C. jejuni






PF-562

S. epidermidis

TPEQWLERSTVVVTGLLNRK
775



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-563

S. epidermidis

RPELDNELDVVQNSASLDKLQASYN
776



M. luteus






C. jeikeium






PF-564

S. epidermidis

TIILNDQINSLQERLNKLNAETDRR
777



C. albicans






S. pneumoniae






C. jeikeium






PF-566

P. mirabilis

EAQQVTQQLGADFNAITTPTATKV
778



S. pneumoniae






PF-567

S. epidermidis

QQRVKAVDASLSQVSTQVSGAVASA
779



P. aeruginosa






C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-568

S. epidermidis

TQAVQVKTAQAQQQ
780



PF-569

M. luteus

KSKISEYTEKEFLEFVEDIYTNNK
781



P. mirabilis






S. pneumoniae






E. faecalis






C. jeikeium






PF-570

S. pneumoniae

KKFPTEESHIQAVLEFKKLTEHPSG
782



C. jeikeium






PF-572

S. epidermidis

WRASKGLPGFKAG
783



M. luteus






E. coli






S. pneumoniae






C. jeikeium






PF-573

S. epidermidis

EKKLIVKLIDSIGKSHEEIVGAG
784



S. pneumoniae






PF-575

M. luteus

LNFRAENKILEKIHISLIDTVEGSA
785



E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-576

M. luteus

AYSGELPEPLVRKMSKEQVRSVMGK
786



P. mirabilis






E. coli






P. aeruginosa






C. albicans






S. pneumoniae






PF-577

S. epidermidis

PFETRESFRVPVIGILGGWDYFMHP
787



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. .faecalis






PF-578

S. epidermidis

QKANLRIGFTYTSDSNVCNLTFALLGSK
788



M. luteus






P. mirabilis






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-579

S. epidermidis

MILVCAAVIWGRVLFILKFPIYFSIRLAF
789



M. luteus

L




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-580

S. epidermidis

EILNNNQVIKELTMKYKTQFESNLGGW
790



M. luteus

TARARR




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-581

S. epidermidis

WTARARR
791



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-583

S. epidermidis

KFQGEFTNIGQSYIVSASHMSTSLNTGK
792



M. luteus






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-584

S. epidermidis

SYIKNLSNQKFLIAF
793



M. luteus






P. mirabilis






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-585

S. epidermidis

DYNHLLNVVQDWVNTN
794



E. coli






C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-586

S. epidermidis

FFNQANYFFKEF
795



M. luteus






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-587

S. epidermidis

ASGKYQSYLLNVYVDSKKDRLDIFDKL
796



M. luteus

KAKAKFVL




E. coli





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-588

S. epidermidis

ESVEAIKAKAIK
797



E. coli






C. albicans






E. faecalis






C. jeikeium






C. jejuni






PF-589

S. epidermidis

APLRIDEIRNSNVIDEVLDCAPKKQEHFF
798



C. albicans

VVPKIIE



MRSA





S. pneumoniae






PF-590

S. epidermidis

YYQAKLFPLL
799



M. luteus






E. coli






E. faecalis






C. jeikeium






PF-592

S. epidermidis

IMKNYKYFKLFIVKYALF
800



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-593

C. jeikeium

MEISTLKKEKLHVKDELSQYLANYKK
801



PF-594

C. jeikeium

IVSAIV
802



PF-595

S. epidermidis

LQNKIYELLYIKERSKLCS
803



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-596

S. epidermidis

SKMWDKILTILILILELIRELIKL
804



M. luteus






P. mirabilis






E. coli






P. aeruginosa





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-597

P. mirabilis

DEIKVSDEEIEKFIKENNL
805



PF-598

S. epidermidis

MKFMLEVRNKAISAYKEITRTQI
806



M. luteus






P. mirabilis






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-599

S. epidermidis

LFEIFKPKH
807



P. mirabilis






E. coli






C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-600

S. epidermidis

TKKIELKRFVDAFVKKSYENYILERELK
808



M. luteus

KLIKAINEELPTK




B. subtilis






P. mirabilis






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-601

C. jeikeium

YRVTVKALE
809



PF-602

P. mirabilis

LEKEKKEYIEKLFKTK
810



C. jeikeium






PF-603

S. epidermidis

IDKLKKMNLQKLSYEVRISQDGKSIYAR
811



M. luteus

IK




B. subtilis






E. coli






P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-604

S. epidermidis

LMEQVEV
812



C. albicans






C. jeikeium






PF-605

S. epidermidis

HYRWNTQWWKY
813



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-607

S. epidermidis

YIESDPRKFDYIFGAIRDH
814



P. mirabilis






E. coli





MRSA





S. pneumoniae






C. jeikeium






PF-609

P. mirabilis

TEIKLDNNEYLVLNLDDILGILK
815



E. coli






S. pneumoniae






PF-610

S. epidermidis

VFLKLKTSKIDLASIIFYP
816



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans






MRSA






S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






PF-612

S. epidermidis

GTTLKYGLERQLKIDIHPEITIINLNGGA
817



M. luteus

DEFAKL




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-613

C. jeikeium

ADEFAKL
818



PF-614

S. epidermidis

GLDIYA
819



E. coli






C. jeikeium






PF-615

S. epidermidis

FLNRFIFYIFTVKTKSALIKNLFLD
820



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






C. jeikeium






C. jejuni






PF-616

C. jeikeium

IVFVVTKEKK
821



PF-617

P. aeruginosa

PMNAAEPE
822



C. albicans






PF-619

S. epidermidis

WSRVPGHSDTGWKVWHRW
823



M. luteus






B. subtilis






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-621

S. epidermidis

PPSSFLV
824



C. albicans






PF-622

S. epidermidis

TREDVFSVRLINNIVNKQA
825



P. aeruginosa






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






PF-623

S. epidermidis

VLFAVYLGALDWLFSWLTQKM
826



P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-625

S. epidermidis

SDSTNNARTRKKARDVTTKDIDK
827



M. luteus






S. pneumoniae






C. jeikeium






PF-626

S. epidermidis

KYDFDDFEPEEA
828



M. luteus






E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-627

S. epidermidis

INDLLSYFTLHEK
829



P. aeruginosa





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-629

S. epidermidis

GLAAIATVFALY
830



P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-630

S. epidermidis

IPATPIIHS
831



M. luteus






P. mirabilis






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-631

S. epidermidis

LIIYFSKTGNTARATRQI
832



P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-632

S. epidermidis

TTIQGVASLEKHGFRYTIIYPTRI
833



P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-634

S. epidermidis

MPKARPVNHNKKKSKITIKSNFTLFYM
834



M. luteus

FNP




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-635

S. epidermidis

MNAHGHSLIFQKMIVHAFAFFSKQKNY
835



P. aeruginosa

LYF




C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-636

S. epidermidis

LVRLA
836



C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-637

S. epidermidis

SRIKQDARSVRKYDRIGIFFYSFKSA
837



P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-638

S. epidermidis

TFILPK
838



C. albicans





MRSA





C. jeikeium






PF-639

S. pneumoniae

QATQIKSWIDRLLVSED
839



C. jeikeium






PF-640

C. albicans

MGDINRNF
840



PF-641

S. epidermidis

SWKCHHLAIGGSWKCHHLAI
841



M. luteus






E. coli






C. albicans





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-642

M. luteus

FTTPMIGIPAGLLGGSYYLKRREEKGK
842


MRSA





C. jeikeium






PF-643
Mycobacteria spp
VRCRL
843



PF-644
Mycobacteria spp
TSGLIIGENGLNGL
844



PF-645
Mycobacteria spp
SNSVQQG
845



PF-646
Mycobacteria spp
APASPGRRPG
846



PF-647
Mycobacteria spp
GTFLGQKCAAATAS
847



PF-648

S. mutans

ARRYPAAGS
848



E. coli






PF-649
Mycobacteria spp
CPRYPFVDVGPAGPWRARWRVGS
849



PF-650
Mycobacteria spp
IRSDQPGRQSRSSPRWPTGAGRHR
850



PF-651
Mycobacteria spp
PRWPTGAGRHR
851



PF-652
Mycobacteria spp
FLAPARPDLQAQRQALAQ
852



PF-653
Mycobacteria spp
QSVHPLPAETPVADVI
853



PF-654
Mycobacteria spp
LSGRLAGRR
854



PF-655

M. smegmatis

DAPCFDDQFGDLKCQMC
855



PF-656
Mycobacteria spp
RGMFVPFHDVDCVQ
856



PF-657
Mycobacteria spp
YVANYTITQFGRDFDDRLAVAIHFA
857



PF-658
Mycobacteria spp
PTTPPPTTPPEIPTGGTVIST
858



PF-659
Mycobacteria spp
TVIST
859



PF-660
Mycobacteria spp
TDPQATAAPRRRTSPR
860



PF-661
Mycobacteria spp
PDEDIRRRAILPPAGPCRPMSPE
861



PF-662
Mycobacteria spp
GKQSRAHGPVASRREFRRKSG
862



PF-663
Mycobacteria spp
ATLIPRKA
863



PF-664

M. smegmatis

DQLCVEYPARVSTG
864



PF-665
Mycobacteria spp
VLRVATAVGEVPTGL
865



PF-666
Mycobacteria spp
PNRRSRPR
866



PF-667
Mycobacteria spp
PAHQRLRIDQRLVADRDMVQDYES
867



PF-668
Mycobacteria spp
TNAESMALAFRGRVHMSVNIAGLT
868



PF-669
Mycobacteria spp
RADRIESYPADGDRVITLWRNPYR
869



PF670
Mycobacteria spp
TVIVAPMHSGV
870



PF-671

S. mutans

TVSAFRTVH
871



E. coli






PF-673

S. mutans

VRRLRM
872



E. coli






PF-674

S. mutans

DGCDSEPALTYR
873



E. coli






PF-675
Mycobacteria spp
EIIPISPTRRCEMHTMSSAEYRGL
874



PF-676

S. mutans

AEYRGL
875



E. coli






PF-677
Mycobacteria spp
TCRGAGMH
876



PF-678
Mycobacteria spp
RDRRWTRRDMYDWLESARV
877



PF-679
S. mutans
CRARFIRR
878


E. coli





PF-680
Mycobacteria spp
ADPHPTTGI
879



PF-681

M. smegmatis

TALTTVGVSGARLITYCVGVEDI
880



PF-682
Mycobacteria spp
RRGKSEQGLSRR
881



PF-683
Mycobacteria spp
LWPVA
882



PF-684
Mycobacteria spp
RKLSLASGFALWRRSLV
883



PF-685
Mycobacteria spp
PTLWLACL
884



PF-686

M. smegmatis

LAVLMGYIGYRGWSGKRHINRQ
885



PF-687
Mycobacteria spp
AKRVLSLAVAPHRRQPVQGT
886



PF-688
Mycobacteria spp
ARNHAVIPAG
887



PF-689

S. mutans

SAPSG
888



E. coli






PF-690
Mycobacteria spp
MIPLAGDPVSSHRTVEFGVLGTYLVSG
889



GSL




PF-691
Mycobacteria spp
HRTVEFGVLGTYLVSGGSL
890



PF-692
Mycobacteria spp
GVAREDPLEPDPLAPIIDDSR
891



PF-693
Mycobacteria spp
PDPAR
892



PF-694
Mycobacteria spp
DLIRPLYSMSAPSVA
893



PF-695
Mycobacteria spp
ALSVMLGNIPLVVPNANQL
894



PF-696
Mycobacteria spp
IRSGISAAYARPLR
895



PF-697
Mycobacteria spp
RADARAK
896



PF-698
Mycobacteria spp
SSGRAGVKCRRPTGR
897



PF-699
Mycobacteria spp
GRAGVKCRRPTGR
898



PF-700
Mycobacteria spp
LNWPFTGR
899



PF-701

S. mutans

PRGAQSGHG
900



PF-702
Mycobacteria spp
LSGRLAGRR
901



PF-703
Mycobacteria spp
MTTVDNIVGLVIAVALMAFLFAALLFPE
902



KF


PF-704
Mycobacteria spp
APAARAAL
903



PF-705

S. mutans

GEEEGTVAD
904



E. coli






PF-706

L. pneumophila

LGYGAWIGCGLGLNGFHRID
905



PF-707

S. mutans

IDPESIVTTNNKQDNVDEQ
906



E. coli






PF-709

S. mutans

NKKHSPMD
907



PF-711

S. mutans

KTAGPTGTIYKTN
908



PF-712

S. mutans

QIYRHVHKVQAKSANLRLY
909



E. coli






PF-714

L. pneumophila

FVVTQRMLRMYKK
910



PF-716

S. mutans

HGENHEIFIKSDEKDNDSSEKKD
911



PF-717

E. coli

PQSEVTFENIYAPKANGGGLYGI
912



PF-720

S. mutans

SLDMGK
913



PF-724

L. pneumophila

CYRFLTPKRPTRIS
914



PF-727

S. mutans

AYARCRHDYPFTLGQMQTH
915



E. coli






PF-728

S. mutans

AIGQEQDRREYYYYSGYPYYY
916



E. coli






PF-731

L. pneumophila

RHKLIRLPLSESVFCFLNNPKI
917



PF-732

E. coli

DRPSQTTHHTLSSSRITGPS
918



PF-733

S. mutans

VISRQMGSEAVLELFIIM
919



E. coli






PF-735

S. mutans

YDPLFPNDKN
920



E. coli






PF-737

S. epidermidis

KSSGSSASASSTAGGSSSK
921



S. pneumoniae






PF-738

S. epidermidis

KSGATSAASGAKSGASS
922



C. albicans






C. jeikeium






PF-741

S. epidermidis

AKREDTVAAQIGANILNLIQ
923



M. luteus






P. mirabilis






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. .faecalis






PF-744

S. epidermidis

LGVGTFVGKVLIKNQQKQKSKKKAQ
924



M. luteus






E. coli





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-745

S. epidermidis

ANSQNSLFSNRSSFKSIFDKKSNITTNAT
925



M. luteus

TPNSNIIIN




C. albicans






PF-746

S. epidermidis

FLGNSQYFTRK
926



M. luteus






E. coli






C. albicans






S. pneumoniae






E. faecalis






C. jeikeium






PF-748

S. epidermidis

FQGFFDVAVNKWWEEHNKAKLWKNV
927



M. luteus

KGKFLEGEGEEEDDE




E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-749

S. epidermidis

GVNKWWEEHNKAKLWKNVKGKFLEG
928



M. luteus

EGEEEDDE




E. coli






P. aeruginosa






C. albicans






S. pneumoniae






C. jeikeium






PF-750

M. luteus

AESSPAKTTA
929



C. jeikeium






PF-751

S. epidermidis

AESSPAQETT
930



E. coli






C. albicans






C. jeikeium






PF-752

S. epidermidis

LHVIRPRPELSELKFPITKILKVNKQGLK
931



E. coli

K



MRSA





S. pneumoniae






E. faecalis






PF-756

S. epidermidis

DALLRLA
932



M. luteus






C. albicans





MRSA





C. jeikeium






PF-757

M. luteus

PQAISSVQQNA
933



C. albicans





MRSA





PF-758

S. epidermidis

PEIIKIVSGLL
934



M. luteus






E. coli





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-760

S. epidermidis

DHITLDDYEIHDGFNFELYYG
935



M. luteus






PF-761

S. epidermidis

SKFELVNYASGCSCGADCKCASETECK
936



M. luteus

CASKK




P. mirabilis






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-762

M. luteus

PAPAPSAPAPAPEQPEQPA
937



C. albicans






PF-763

S. epidermidis

GIWMARNYFHRSSIRKVYVESDKEYER
938



M. luteus

VHPMQKIQYEGNYKSQ




E. coli






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-764

S. epidermidis

GYFEPGKRD
939



M. luteus






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-765

S. epidermidis

YLYWEVEHKPIIAKRDAYYAQLRKQKE
940



M. luteus

IEEGA




E. coli





MRSA





E. faecalis






C. jeikeium






PF-766

S. epidermidis

DAYYAQLRKQKEIEEGA
941



M. luteus






C. albicans






MRSA






E. faecalis






C. jeikeium






PF-767

S. epidermidis

DGKQGEPVALKPTDN
942



M. luteus






E. coli





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-768

S. epidermidis

GFRGGKRGGARG
943



S. pneumoniae






E. faecalis






C. jeikeium






PF-770

S. epidermidis

GVGIGFIMMGVVGYAVKLVHIPIRYLIV
944



M. luteus






P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






PF-772

S. epidermidis

TKESSS
945



C. albicans





MRSA





S. pneumoniae






C. jeikeium






PF-773

S. epidermidis

TLKESK
946



C. albicans






C. jeikeium






PF-776

S. epidermidis

VSILLYLSATIMPNVLRLLVARAIIVRV
947



M. luteus






P. mirabilis






C. albicans





MRSA





S. pneumoniae






E. faecalis






PF-777
Mycobacteria spp.
PGADGKLAEASAAIARLVRS
948



PF-778
Mycobacteria spp.
MNLILTAHGT
949



PF-779
Mycobacteria spp.
IYGDFFNFYLCDISLKVNGLQPGGPVRT
950



VKLFGQPTGRCTPQ




PF-780
Mycobacteria spp.
AVYDALVALAAAEHRAELATRDARAK
951



DTYEKIGVHVVVAA




PF-781
Mycobacteria spp.
PLVVVNHRRAERSRG
952



PF-782
Mycobacteria spp.
TGPRRGIDLTSNRALSEVLDEGLELNSR
953



K




PF-783
Mycobacteria spp.
FTSEVRGVFTYRVNKAGLITNMRGYW
954



NLDMMTFGNQE




PF-784
Mycobacteria spp.
MAMTTVDNIVGLVIAVALMAFLFAALL
955



FPEKF




PF-785
Mycobacteria spp.
MRPQHSPAGKAFVVKKITHEQS
956



PF-786
Mycobacteria spp.
LSERERRRLKRGII
957



PF-787
Mycobacteria spp.
MTERQRRALLKQHPEVVSWSDYLEKR
958



KRRTGTAG




PF-788
Mycobacteria spp.
GLITVFAGTARILQLRRAAKKTHAAAL
959



R


PF-789
Mycobacteria spp.
PRGAQSGHG
960



PF-790
Mycobacteria spp.
PAGPDHLDQRDHR
961



PF-791

S. mutans

IFLTTQNTDYSEHNAA
962



PF-792

S. mutans

ALHASGIQAI
963



PF-793

S. mutans

YTQUNNASAYAMLLTNKDTVP
964



PF-794

S. mutans

NLYFENQGN
965



PF-795

S. mutans

ALHKSGIQVIADWVPDQIYN
966



PF-796

S. mutans

YTQSNIPTAYALMLSNKDSI
967



PF-797

S. mutans

WYYFDNNGYM
968



PF-798

S. mutans

ALHSKGIKVMADWVPDQMYA
969



PF-799

S. mutans

YTHYNTALSYALLLTNKSSVP
970



PF-800

S. mutans

WYYFDNNGYM
971



PF-0003

A. naeslundii

FCSVDHDVITIAADHVKQGAEA
972



P. gingivalis






S. mutans






PF-0008

A. naeslundii

AQPRRTWLVNFGEVPSPGLTNDGMPDH
973



PF-0034

S. mutans

HPMPITVRSRKPGPLTAPSEH
974



E. coli






PF-0045

A. naeslundii

FREGMGWPLSNEGSPTAPLPKHRNQV
975



T. denticola






PF-0050

A. naeslundii

QGLARPVLRRIPL
976



S. mutans






PF-0052

A. naeslundii

SRFRNGV
977



F. nucleatum






S. mutans






PF-0055

A. naeslundii

YNLSIYIYFLHTITIAGLITLPFII
978



F. nucleatum






P. gingivalis






S. mutans






PF-0057

A. naeslundii

YFWWYWVQDCIPYKNNEVWLELSNN
979



F. nucleatum

MK




P. gingivalis






S. mutans






PF-0058

A. naeslundii

FETGFGDGYYMSLWGLNEKDEVCKVV
980



F. nucleatum

IPFINPELID




P. gingivalis






S. mutans






PF-0061

A. naeslundii

TLNYKKMFFSVIFLLGLNYLICNSPLFFK
981



F. nucleatum

QIEF




P. gingivalis






S. mutans






T. denticola






PF-0062

A. naeslundii

PLARATEVVATLFIICSLLLYLTR
982



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-0063

A. naeslundii

SHFRKGD
983



F. nucleatum






S. mutans






PF-0064

A. naeslundii

DEEALEMGANLYAQFAIDFLNSKK
984



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-0065

A. naeslundii

DEERYSDSYFLKEKVFYLILALFLILFHQ
985



F. nucleatum

KYLYFLEIITI




P. gingivalis






S. mutans






PF-0068

A. naeslundii

LNLFASI
986



F. nucleatum






S. mutans






PF-0069

A. naeslundii

NALMLREMQLAKNIKVEVTDVLSNKK
987



F. nucleatum

YC




P. gingivalis






S. mutans






T. denticola






PF-0071

A. naeslundii

QVIVKIL
988



F. nucleatum






S. mutans






PF-0072

A. naeslundii

KKMFSLIRKVNWIFFILFIVLDLTNVFPLI
989



F. nucleatum

RTILFAILSRQ




P. gingivalis






S. mutans






T. denticola






PF-0075

A. naeslundii

KALVISVFAIVFSIIFVKFFYWRDKK
990



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-0080

A. naeslundii

INIPGLF
991



F. nucleatum






S. mutans






PF-0084

A. naeslundii

FFSVIFLFGLNYLICNSPLFNILR
992



F. nucleatum






P. gingivalis






S. mutans






PF-0085

A. naeslundii

KKFKIFVIINWFYHKYIILNFEENF
993



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-0086

A. naeslundii

ELFFTILSDCNELFLLHLLQQPLFYIKKG
994



F. nucleatum

K




P. gingivalis






S. mutans






T. denticola






PF-0088

A. naeslundii

DIANNILNSVSERLIIA
995



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-0091

A. naeslundii

ASNTPRFVRLTLFNFYSKIWNVTHLFLF
996



F. nucleatum

NNL




P. gingivalis






S. mutans






T. denticola






PF-0093

A. naeslundii

EKLGTMV
997



F. nucleatum






S. mutans






PF-0095

A. naeslundii

LLALNIVINEDTYYFELFFIFDNQNKKWL
998



F. nucleatum

IFDLKERG




P. gingivalis






S. mutans






PF-0098

A. naeslundii

PETKGKVSAFVFGIVVANVIAVVYILYM
999



F. nucleatum

LREIGIIQ




P. gingivalis






S. mutans






T. denticola






PF-C120

A. naeslundii

ASLSTMTFKVMELKELIILLCGLTMLMI
1000



F. nucleatum

QTEFV




P. gingivalis






S. mutans






T. denticola






PF-C131

A. naeslundii

QWIVAKREIRMHIYCHISVIHVIIFFG
1001



F. nucleatum






P. gingivalis






S. mutans






PF-C134

A. naeslundii

NELMKYPATLTATATTPGIKYSHLCSVC
1002



F. nucleatum

L




P. gingivalis






S. mutans






T. denticola






PF-C135

A. naeslundii

KNTHAYLRVLRLSSLILSYQASVYPLFA
1003



F. nucleatum

YLCQQKDY




P. gingivalis






S. mutans






PF-C136

A. naeslundii

LILSYQASVYPLFAYLCQQKDY
1004



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C137

A. naeslundii

QRMYWFKRGFETGDFSAGDTFAELK
1005



F. nucleatum






P. gingivalis






S. mutans






PF-C139

A. naeslundii

LLASHPERLSLGVFFVYRVLHLLLENT
1006



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C142

A. naeslundii

DFPPLSFFRRRFHAYTAPIDNFFGANPF
1007



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C143

A. naeslundii

VVFGGGDRLV
1008



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C145

A. naeslundii

YGKESDP
1009



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C160

F. nucleatum

AASGFTYCASNGVWHPY
1010



PF-C180

F. nucleatum

TVEELDKAFTWGAAAALAIGVIAINVG
1011



P. gingivalis

LAAGYCYNNNDVF




S. mutans






T. denticola






PF-C181

P. gingivalis

KMRAGQVVFIYKLILVLLFYVLQKLFD
1012



LKKGCF




PF-C194

A. naeslundii

NTNDLLQAFELMGLGMAGVFIVLGILYI
1013



F. nucleatum

VAELLIKIFPVNN




P. gingivalis






S. mutans






T. denticola






PF-C259

F. nucleatum

AEIQPHCLSVL
1014



S. mutans






PF-C271

A. naeslundii

FFPSYYSIIITYF
1015



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C273

A. naeslundii

KNMLKRRMKQKRLFDEEDRLRVLSKY
1016



P. gingivalis

TKSYY




S. mutans






T. denticola






PF-C281

A. naeslundii

KKEKLLTAIRLQHRAEIRGYFTIFFLFFRI
1017



F. nucleatum






P. gingivalis






S. mutans






T. denticola






PF-C285

A. naeslundii

FTIIELKKQKIKHGENNKKTAHPLNEPF
1018



F. nucleatum

CARA




P. gingivalis






S. mutans






T. denticola






PF-C290

A. naeslundii

GNVHPESDFHNLIQFIKTFLYFTIFFKYF
1019



F. nucleatum

L




P. gingivalis






S. mutans






T. denticola






PF-C291

A. naeslundii

HPFLTGTGCPLFLIFRLFFVKAYFSFTVF
1020



F. nucleatum






P. gingivalis






S. mutans






PF-S003

S. epidermidis

ALALLKQDLLNFEGRGRIITSTYLQFNE
1021



M. luteus

GCVP




P. mirabilis






E. coli






P. aeruginosa






C. albicans





MRSA





S. pneumoniae






E. faecalis






C. jeikeium






C. jejuni






M. smegmatis






PF-S004

S. epidermidis

VLLNIFRTLLEFFSPSNAPGAEDVPLPDT
1022


MRSA
QA




C. jeikeium






PF-S007

S. epidermidis

VVAGVVLLTALAVGSKRKEKKQIKEIQ
1023


MRSA
RLLAATR




PF-S015

S. epidermidis

IENLERGARRPP
1024


MRSA





C. jeikeium






PF-S018

S. epidermidis

GMPQIPRLRI
1025



M. luteus






C. albicans





MRSA





E. faecalis






C. jeikeium






C. jejuni






PF-S023

S. epidermidis

MAEDERRALKRRTNRGRTRTRKRITV
1026


MRSA





PF-S026

S. epidermidis

TELKYNGEEYLLLTQRDILAVIEK
1027


MRSA





C. jeikeium






PF-S029

M. luteus

TSDTQSQSPWLFDNADIVNIYPVQLMHS
1028



P. mirabilis

SDND




E. coli






C. albicans






C. jeikeium






C. jejuni




*Peptide binding was conducted in aqueous buffers that varied depending on peptidesolubility. For example: Brain Heart Infusion (BHI) Media; 1X Phosphate-buffered saline(PBS); 0.05% v/v Tween-20; 0.05% v/v Tween-80; 1% v/v Glycerol; 50 μM Guanidine hydrochloride; 0.05% v/v Acetic acid; 50 Urea; 1% v/v Polyethylene glycol 400 (PEG 400); 20 mM Sodium glutamate; 50 μM Piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES); 50 mM Sodium acetate; 1% v/v Pluronic 17R4; 1% w/v Pluronic F108; 1% w/v Pluronic P123; 0.2% v/v Cetyl trimethylammonium bromide (CTAB); 0.8% v/v β-D-Octyl glucoside (BOG); 0.2% CTAB and 0.05% Tween-20; 0.2% CTAB and 0.05% Tween-80; 0.2% CTAB and 1% glycerol; and 20 mM HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid), 150 mM sodium chloride, 1mM magnesium chloride and 0.1% CTAB. Preferably, binding was evaluated in lx PBS.

**Three-amino acid code: Dab: Diaminobutyric acid; Orn: Ornithine; cDOrn, cOrn: side- chain cyclical Ornithine; Abreviations: c(X...Y) indicates amino acids are cyclic, connected X to Y; DX indicates D-isoform amino acids.






































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































In certain embodiments, the amino acid sequence of the targeting peptides comprises or consists of a single amino acid sequence, e.g., as listed above in Table 3. In certain embodiments the amino acid sequence of the targeting peptides comprises two copies, three copies, four copies, five copies six copies or more of one or more of the amino acid sequences listed in Table 3, and/or Table 10, and/or Table 12. Thus, compound targeting constructs are contemplated where the construct comprises multiple domains each having targeting activity. The targeting domains comprising such a construct can be the same or different. In certain embodiments the construct comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 different targeting domains each domain comprising a different targeting sequence.
Various targeting domains comprising such a construct can be joined directly to each other or two or more of such domains can be attached to each other via a linker. An illustrative, but non-limiting, list of suitable linkers is provided in Table 16. Thus, in certain embodiments, two or more targeting domains comprising a compound/multiple targeting construct are chemically conjugated together.
In certain embodiments the two or more targeting domains comprising the construct are joined by a peptide linker. Where all the targeting domains are attached directly to each other or are joined by peptide linkers, the entire construct can be provided as a single-chain peptide (fusion protein).
In various embodiments, the targeting peptides described herein comprise one or more of the amino acid sequences shown in Table 3, and/or Table 10, and/or Table 12 (and/or the retro, inverso, retroinverso, etc. forms of such sequences). In certain embodiments the peptides range in length up to about 100 amino acids in length, preferably up to about 80, about 70, about 60, or about 51 amino acids in length. In certain embodiments the peptides range in length from about 8 amino acids up to about 100 amino acids 80 amino acids, 60 amino acids or about 51 amino acids in length. In certain embodiments the peptides range in length from about 8 up to about 50, 40, 30, 20, 15, 15, 13, or 12 amino acids in length.
As shown in Tables 3, 10, and 12 the various amino acid sequences described herein target particular microorganisms. The range of activity of the peptides or compositions comprising such peptides can be increased by including amino acid sequences that target different microorganisms either as separate components and/or as multiple domains within a single construct.
In some embodiments greater specificity and/or avidity can be obtained by including multiple different amino acid sequences that target the same microorganism.
II. Antimicrobial Peptides.
A) Uses of Antimicrobial Peptides.
The antimicrobial peptides described herein also have a wide variety of uses. For example, the peptides can be formulated individually, in combination, in combination with other antimicrobial peptides, and/or in combination with various antibacterial agents to provide antimicrobial pharmaceuticals.
In various embodiments, the antimicrobial peptides described herein can be formulated individually, in combination, in combination with other antimicrobial peptides, and/or in combination with various antibiotic (e.g., antibacterial) agents in “home healthcare” formulations. Such formulations include, but are not limited to toothpaste, mouthwash, tooth whitening strips or solutions, contact lens storage, wetting, or cleaning solutions, dental floss, toothpicks, toothbrush bristles, oral sprays, oral lozenges, nasal sprays, aerosolizers for oral and/or nasal application, wound dressings (e.g., bandages), and the like.
In various embodiments the antimicrobial peptides described herein can be formulated individually, in combination, in combination with other antimicrobial peptides, and/or in combination with various antibiotic (e.g., antibacterial) agents in various cleaning and/or sterilization formulations for use in agriculture, in fool preparation and transport, in the home, workplace, clinic, or hospital.
In certain embodiments the antimicrobial peptides described herein are attached to one or more targeting moieties to specifically and/or to preferentially deliver the peptide(s) to a target (e.g. a target microorganism, biofilm, bacterial film, particular tissue, etc.).
Other possible uses of the targeting and/or antimicrobial peptides disclosed herein include, but are not limited to biofilm dispersal, biofilm retention, biofilm formation, anti-biofilm formation, cell agglutination, induction of motility or change in motility type, chemoattractant or chemorepellent, extracellular signal for sporogenesis or other morphological change, induction or inhibition of virulence gene expression, utilized as extracellular scaffold, adhesin or binding site, induction or suppression of host immune response, induction or suppression of bacterial/fungal antimicrobial molecule production, quorum-sensing, induction of swarming behavior, apoptosis or necrosis inducing in eukaryotic cells, affecting control of or inducing the initiation of cell cycle in eukaryotes, in archaea or prokaryotes, induces autolysis or programmed cell death, inhibition of phage/virus attachment or replication, evasion of innate immunity, induction or inhibition of genetic transformation or transduction competence, induction or inhibition of pilus-mediated conjugation, induction or inhibition of mating behavior in bacteria and fungi, induction or inhibition of nodule formation or metabolic compartmentalization, metal, ion, or nutrient binding, acquisition or inhibition of metal, ion, or nutrient binding and acquisition, and the like.
In certain embodiments, compositions and methods are provided for decreasing the infectivity, morbidity, and rate of mortality associated with a variety of pathogens. The present invention also relates to methods and compositions for decontaminating areas, samples, solutions, and foodstuffs colonized or otherwise infected by pathogens and microorganisms. Certain embodiments of the present compositions are nontoxic and may be safely ingested by humans and other animals. Additionally, certain embodiments of the present invention are chemically stable and non-staining.
In some embodiments, the present invention provides compositions and methods suitable for treating animals, including humans, exposed to pathogens or the threat of pathogens. In some embodiments, the animal is contacted with effective amounts of the compositions prior to exposure to pathogenic organisms. In other embodiments, the animal or human is contacted with effective amounts of the compositions after exposure to pathogenic organisms. Thus, the present invention contemplates both the prevention and treatment of microbiological and other infections.
In certain embodiments compositions and methods are provided for decontaminating solutions and surfaces, including organic and inorganic samples that are exposed to pathogens or suspected of containing pathogens. In still other embodiments of the present invention, the compositions are used as additives to prevent the growth of harmful or undesired microorganisms in biological and environmental samples.
These applications of the peptides described herein are intended to be illustrative and not limiting. Using the teaching provided herein, other uses will be recognized by one of skill in the art.
B Illustrative Novel Antimicrobial Peptides.
Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Unmodified, these peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram-negative and Gram-positive bacteria (including strains that are resistant to conventional antibiotics), mycobacteria (including Mycobacterium tuberculosis ), enveloped viruses, and fungi.
Naturally-occurring antimicrobial peptides are typically short peptides, generally between 12 and 50 amino acids. These peptides often include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and frequently a large proportion (generally >50%) of hydrophobic residues (see, e.g., Papagianni et al. (2003) Biotechnol Adv 21: 465; Sitaram and Nagaraj (2002) Curr Pharm Des 8: 727; Durr et al. (2006) Biochim. Biophys. Acta 1758: 1408-1425).
Frequently the secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-stranded due to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended. Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. The ability to associate with membranes is a definitive feature of antimicrobial peptides although membrane permeabilisation is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.
The modes of action by which antimicrobial peptides kill bacteria is varied and includes, but is not limited to disrupting membranes, interfering with metabolism, and targeting cytoplasmic components. In many cases the exact mechanism of killing is not known.
In certain embodiments the antimicrobial peptides include peptides comprising or consisting of one or more of the amino acid sequences shown in Tables 4 (SEQ ID NOs:1029-1078), and/or Table 5 (SEQ ID NOs:1079-1566). In various embodiments the peptides include peptides comprising or consisting of the retro, inverso, retro-inverso, and/or beta form of one or more of the amino acid sequences shown in Tables 4 (SEQ ID NOs:1029-1078), and/or Table 5 (SEQ ID NOs:1079-1566). The peptides can comprise all “L” amino acids, all “D” amino acids, or combinations of “L” and “D” amino acids. Also contemplated are circular permutations of these sequences as well as peptides comprising or consisting of the retro, inverso, retro-inverso, and/or beta form of such circular permutations.
It will also be recognized, that in certain embodiments, any peptide or compound AMP described herein can be circularized.
In various embodiments the peptides can optionally bear one or more protecting groups, e.g., and the amino and/or carboxyl termini, and/or on side chains.
Also contemplated are peptides comprising one, two, three four, or five conservative substitutions of these amino acid sequences.
TABLE 4 Novel antimicrobial peptides, target microorganisms and MIC values. Organism MIC SEQ ID (μM) Structure/sequence ID NO K-1 S. mutans , 25 GLGRVIGRLIKQIIWRR 1029 K-2 S. mutans , 12.5 VYRKRKSILKIYAKLKGWH 1030 K-7 S. mutans , 12.5 NYRLVNAIFSKIFKKKFIKF 1031 K-8 S. mutans , 4 KILKFLFKKVF 1032 K-9 S. mutans , 4 FIRKFLKKWLL 1033 K-10 S. mutans , 4 KLFKFLRKHLL 1034 K-11 S. mutans , 4 KILKFLFKQVF 1035 K-12 S. mutans , 8 KILKKLFKFVF 1036 K-13 S. mutans , 16 GILKKLFTKVF 1037 K-14 S. mutans , 8 LRKFLHKLF 1038 K-15 S. mutans , 4 LRKNLRWLF 1039 K-16 S. mutans , 8 FIRKFLQKLHL 1040 P. aeruginosa , 12.5 MRSA, 25 K-17 S. mutans , 8 FTRKFLKFLHL 1041 K-18 S. mutans , 16 KKFKKFKVLKIL 1042 K-19 S. mutans , 16 LLKLLKLKKLKF 1043 K-20 S. mutans , 8 FLKFLKKFFKKLKY 1044 K-21 S. mutans , 8 GWLKMFKKIIGKFGKF 1045 K-22 S. mutans , 8 GIFKKFVKILYKVQKL 1046 1T-88 GRLVLEITADEVKALGEALANAKI 1047 PF-531 A. baumannii , 25 YIQFHLNQQPRPKVKKIKIFL-NH2 1048 P. aeruginosa , 50 T. rubrum , 50 A. niger, 25 B. subtilis , 25 C. difficile , 12.5 C. jeikeium , 6.25 S. epidermidis , 50 S. mutans , 12.5 PF-527 P. aeruginosa , 50 GSVIKKRRKRMAKKKHRKLLKKTRIQR 1049 T. rubrum , 25 RRAGK A. niger , 50 B. subtilis , 12.5 C. jeikeium , 6.25 MRSA, 50 S. epidermidis , 25 PF-672 C. albicans , 1.56 MRFGSLALVAYDSAIKHSWPRPSSVRR 1050 T. rubrum , 0.78 LRM A. niger , 3 B. subtilis , 0.78 E. faecalis , 3.13 MRSA, 1.56 S. epidermidis , 0.39 PF-606 E. coli , 50 FESKILNASKELDKEKKVNTALSFNSHQ 1051 MRSA, 50 DFAKAYQNGKI S. epidermidis , 50 S. mutans , 50 S. pneumoniae , 50 PF-547 T. rubrum , 25 WSRVPGHSDTGWKVWHRW-NH2 1052 B. subtilis , 25 S. mutans , 12.5 PF-006 A. baumannii , 50 MGIIAGIIKFIKGLIEKFTGK 1053 B. subtilis , 25 MRSA, 50 PF-545 A. niger , 50 RESKLIAMADMIRRRI-NH2 1054 B. subtilis , 25 MRSA, 50 PF-278 C. albicans , 50 L SLATFAKIFMTRSNWSLKRFNRL 1055 T. rubrum , 50 S. epidermidis , 50 PF-283 T. rubrum , 50 MIRIRSPTKKKLNRNSISDWKSNTSGRF 1056 B. subtilis , 50 FY S. epidermidis , 50 PF-307 C. albicans , 50 MKRRRCNWCGKLFYLEEKSKEAYCCK 1057 T. rubrum , 50 ECRKKAKKVKK B. subtilis , 50 PF-168 T. rubrum , 50 VLPFPAIPLSRRRACVAAPRPRSRQRAS 1058 A. niger , 50 MRSA, 50 PF-538 A. baumannii , 25 KNKKQTDILEKVKEILDKKKKTKSVGQ 1059 C. difficile , 25 KLY PF-448 A. niger , 25 SLQSQLGPCLHDQRH 1060 S. pneumoniae , 50 PF-583 MRSA, 50 KFQGEFTNIGQSYIVSASHMSTSLNTGK 1061 S. epidermidis , 50 PF-600 E. coli , 50 TKKIELKRFVDAFVKKSYENYILERELK 1062 S. pneumoniae , 50 KLIKAINEELPTK PF-525 A. niger , 50 KFSDQIDKGQDALKDKLGDL 1063 S. pneumoniae , 50 PF-529 A. niger , 50 LSEMERRRLRKRA-NH2 1064 S. pneumoniae , 50 PF-148 A. niger , 50 RRGCTERLRRMARRNAWDLYAEHFY 1065 B. subtilis , 50 PF-530 A. baumannii , 25 SKFKVLRKIIIKEYKGELMLSIQKQR 1066 PF-522 C. difficile , 25 FELVDWLETNLGKILKSKSA-NH2 1067 PF-497 B. subtilis , 50 LVLRICTDLFTFIKWTIKQRKS 1068 PF-499 B. subtilis , 50 VYSFLYVLVIVRKLLSMKKRIERL 1069 PF-322 B. subtilis , 50 GIVLIGLKLIPLLANVLR 1070 PF-511 S. pneumoniae , 50 VMQSLYVKPPLILVTKLAQQN 1071 PF-512 S. pneumoniae , 50 SFMPEIQKNTIPTQMK 1072 PF-520 S. pneumoniae , 50 LGLTAGVAYAAQPTNQPTNQPTNQPTN 1073 QPTNQPTNQPRW-NH2 PF-521 S. pneumoniae , 50 CGKLLEQKNFFLKTR 1074 PF-523 S. pneumoniae , 50 ASKQASKQASKQASKQASKQASRSLKN 1075 HLL PF-524 S. pneumoniae , 50 PDAPRTCYHKPILAALSRIVVTDR 1076 PF-209 MRSA, 50 NYAVVSHT 1077 PF-437 S. pneumoniae , 50 FQKPFTGEEVEDFQDDDEIPTII 1078
Where protecting groups are shown (e.g., —NH 2 ) they are optional. Conversely any peptide shown without protecting groups can bear one or more such groups.

In certain embodiments peptides that induce alterations in phenotype or other biological activities can also be used as antimicrobial effector moieties. Illustrative alternative peptides are shown in Table 5.





TABLE 5



Illustrative list of novel morphology, biofilm and growth disrupting peptides.









SEQ ID

ID
Organism, effect
Structure/sequence
NO



G-1
S. mutans : Ca2
DSSQSDSDSDSNSSNTNSNSSITNG
1079


binding





G-2
S. mutans : biofilm
LPGTLHIQAEFPVQLEAGSLIQIFD
1080


structure





G-4
S. mutans :
EIPIQLANDLANYYDISLDSIFFW
1081


Biofilm structure





G-5
M. xanthus :
RDMTVAGKRPNFLIITTDEE
1082


Altered cell




morphology





G-6
M. xanthus :
NTSIVCAVTFAPIKEVPLLWRAGLTLRS
1083


Altered cell
RQS



morphology





G-7
M. xanthus :
QAKVEREVERDLVYTLRRLCDPSGSER
1084


Altered cell
TK



morphology





G-8
S. mutans :
PRMIDIISFHGCHGDHQVWTDPQATAL
1085


Altered biofilm
PR



structure





PF-001
S. epidermidis (C)
MNNWIIVAQLSVTVINEIIDIMKEKQKG
1086


M. luteus (C)
GK



MRSA (R)




C. jeikeium (D)





PF-002
B. subtilis (R)
NDDAQ
1087


S. pneumoniae (H)





PF-003
S. epidermidis (D)
MNNWIKVAQISVTVINEVIDIMKEKQN
1088


M. luteus (A)
GGK



MRSA (R)




C. jeikeium (A)





PF-004
S. epidermidis (A)
ARLSKAIIIAVIVVYHLDVRGLF
1089


M. luteus (A)




MRSA (R)




C. jeikeium (A)





PF-005
B. subtilis (C)
MESIFKIKLMNGICRSENMNMKKKNK
1090


S. pneumoniae (H)
GEKI




PF-006
S. epidermidis (D)
MGIIAGIIKFIKGLIEKFTGK
1091


M. luteus (A)




B. subtilis (I)




MRSA (I)




S. pneumoniae (R)




C. jejuni (D)





PF-007
S. epidermidis (A)
MGIIAGIIKVIKSLIEQFTGK
1092


M. luteus (A)




E. coli (A)




MRSA (R)




E. faecalis (A)





PF-008
B. subtilis (D)
MIEIGSIAYLNGGSKKYNHILNQENR
1093


C. jejuni (R)





PF-009
S. epidermidis (S)
SKKYNHILNQENR
1094



PF-010
S. epidermidis (S)
MDIDVNKLLQAFVYFKSFEKLRHNNS
1095


M. luteus (A)




MRSA (R)




C. jeikeium (A)





PF-011
MRSA (R)
MFCYYKQHKGDNFSIEEVKNIIADNEM
1096


C. jeikeium (C)
KVN




PF-012
S. epidermidis (S)
WRGPNTEAGGKSANNIVQVGGAPT
1097


M. luteus (C)




MRSA (R)




C. jeikeium (A)





PF-013
S. epidermidis (C)
LIQKGLNQTFIVVIRLNNFIKKS
1098


M. luteus (D)




MRSA (R)




C. jeikeium (D)





PF-015
MRSA (W)
SIDKRNLYNLKYYE
1099



PF-017
MRSA (M)
ESIIE
1100



PF-019
MRSA (M)
NDTNK
1101



PF-020
S. mutans (F)
MKIILLLFLIFGFIVVVTLKSEHQLTLFSI
1102


S. epidermidis (C)




M. luteus (C)




MRSA (C)




S. pneumoniae (D)





PF-021
S. epidermidis (A)
FSLNFSKQKYVTVN
1103


M. luteus (A)




MRSA (R)




C. jeikeium (R)





PF-022
S. epidermidis (D)
MINELKNKNSGIMNNYVVTKESKL
1104


M. luteus (A)




MRSA (R)




C. jeikeium (A)





PF-023
MRSA (S)
MTKNTIISLENEKTQINDSENESSDLRK
1105



AK




PF-024
S. epidermidis (D)
DLRKAK
1106


MRSA (M)





PF-025
S. epidermidis (S)
LLIIFRLWLELKWKNKK
1107


M. luteus (A)




MRSA (R)




C. jeikeium (A)





PF-026
MRSA (M)
SIHFIN
1108



PF-027
S. epidermidis (D)
HNARKYLEFISQKIDGDKLTKEDSL
1109


MRSA (M)





PF-028
S. epidermidis (M)
ALDCSEQSVILWYETILDKIVGVIK
1110


MRSA (R)




C. jeikeium (M)





PF-029
MRSA (M)
NSTNE
1111



PF-030
S. epidermidis (D)
MTCHQAPTTTHQSNMA
1112


M. luteus (C)




MRSA (R)




C. jeikeium (C)





PF-031
MRSA (M)
MPHHSTTSSRIVVPAHQSNMASTPNLSI
1113



TP




PF-032
S. epidermidis (S)
RIVVPAHQSNMASTPNLSITP
1114


C. jeikeium (C)





PF-033
S. epidermidis (M)
MFIFKTTSKSHFHNNVKSLECIKIPINK
1115


B. subtilis (C)
NR



MRSA (M)




S. pneumoniae (R)




C. jeikeium (D)




C. jejuni (R)





PF-034
S. epidermidis (A)
EPKKKHFPKMESASSEP
1116



PF-035
MRSA (M)
SFYESY
1117



PF-036
S. epidermidis (S)
ILNRLSRIVSNEVTSLIYSLK
1118


M. luteus (A)




MRSA(R)




C. jeikeium (A)





PF-037
S. epidermidis (D)
MTKKRRYDTTEFGLAHSMTAKITLHQ
1119


M. luteus (C)
ALYK



MRSA (R)




C. jeikeium (D)





PF-040
S. mutans (F)
MIHLTKQNTMEALHFIKQFYDMFFILN
1120


S. epidermidis (D)
FNV



M. luteus (D)




B. subtilis (D)




P. mirabilis (C)




E. coli (C)




MRSA (D)




S. pneumoniae (D)




C. jeikeium (D)




C. jejuni (D)





PF-041
S. epidermidis (R)
ELLVILPGFI
1121


MRSA (M)





PF-042
S. epidermidis (D)
LLSYFRYTGALLQSLF
1122


M. luteus (C)




MRSA (R)




C. jeikeium (S)





PF-043
S. epidermidis (D)
MIKNETAYQMNELLVIRSAYAK
1123


M. luteus (C)




MRSA (R)




C. jeikeium (A)





PF-045
MRSA (S)
LDINDYRSTY
1124



PF-046
S. epidermidis (C)
LDFYLTKHLTLML
1125


MRSA (R)




C. jeikeium (R)





PF-048
S. epidermidis (D)
LYFAFKKYQERVNQAPNIEY
1126


MRSA (W)




C. jeikeium (S)





PF-049
MRSA (S)
AYYLKRREEKGK
1127



PF-051
S. mutans (D)
RFFNFEIKKSTKVDYVFAHVDLSDV
1128


S. epidermidis (D)




M. luteus (C)




MRSA (D)




S. pneumoniae (D)





PF-052
S. epidermidis (S)
QELINEAVNLLVKSK
1129


M. luteus (A)




MRSA (R)




C. jeikeium (D)





PF-053
S. epidermidis (C)
KLFGQWGPELGSIYILPALIGSIILIAIVT
1130


M. luteus (D)
LILRAMRK



B. subtilis (H)




E. coli (A)




P. aeruginosa (A)




C. albicans (A)




MRSA (D)




S. pneumoniae (S)




E. faecalis (A)




C. jeikeium (D)




C. jejuni (D)





PF-056
S. epidermidis (D)
AEQLFGKQKQRGVDLFLNRLTIILSILF
1131


M. luteus (D)
FVLMICISYLGM



B. subtilis (C)




C. albicans (B)




MRSA (M)




S. pneumoniae (D)




C. jeikeium (S)




C. jejuni (D)





PF-057
S. epidermidis (D)
TMIVISIPRFEEYMKARHKKWM
1132


M. luteus (C)




E. coli (M)




C. albicans (A)




MRSA (M)




S. pneumoniae (R)




E. faecalis ( A)




C. jeikeium (A)




C. jejuni (D)





PF-058
MRSA (M)
FADQSQDNA
1133



PF-059
C. jejuni (C)
TITLKAGIERALHEEVPGVIEVEQVF
1134



PF-061
S. epidermidis (R)
GYNSYKAVQDVKTHSEEQRVTAKK
1135


B. subtilis (R)




S. pneumoniae (R)




C. jejuni (R)





PF-063
S. epidermidis (R)
IAAIIVLVLFQKGLLQIFNWILIQLQ
1136


M. luteus (R)




B. subtilis (C)




P. aeruginosa (A)




MRSA (M)




S. pneumoniae (D)




C. jeikeium ( D)




C. jejuni (D)





PF-064
S. epidermidis (D)
DYYGKE
1137


MRSA (M)





PF-065
S. epidermidis (D)
LEKNTRDNYFIHAIDRIYINTSKGLFPES
1138


MRSA (R)
ELVAWG



C. jeikeium (A)





PF-066
MRSA (S)
IKGTVKAVDETTVVITVNGHGTELTFE
1139



KPAIKQVDPS




PF-067
S. epidermidis (D)
DLIVKVHICFVVKTASGYCYLNKREAQ
1140


M. luteus (R)
AAI



B. subtilis (C)




P. aeruginosa (A)




MRSA (M)




S. pneumoniae (D)




C. jeikeium (D)




C. jejuni (D)





PF-068
S. epidermidis (M)
SHLINNFGLSVINPSTPICLNFSPVFNLL
1141


M. luteus (D)
TVYGITCN



B. subtilis (A)




E. coli (A)




MRSA (M)




S. pneumoniae (D)




E. faecalis (A)




C. jeikeium (R)




C. jejuni (D)





PF-069
B. subtilis (D)
FDPVPLKKDKSASKHSHKHNH
1142


C. jejuni (R)





PF-070
B. subtilis (D)
SMVKSEIVDLLNGEDNDD
1143



PF-071
S. epidermidis (R)
HCVIGNVVDIANLLKRRAVYRDIADVI
1144


M. luteus (R)
KMR



B. subtilis (D)




C. albicans (B)




MRSA (C)




S. pneumoniae (A)




C. jejuni (A)





PF-073
S. epidermidis (R)
CPSVTMDACALLQKFDFCNNISHFRHF
1145


M. luteus (R)
FAIKQPIER



MRSA (M)




S. pneumoniae (D)




C. jeikeium (D)




C. jejuni (D)





PF-074
S. epidermidis (D)
RDIHPIYFMTKD
1146


MRSA (M)





PF-075
S. epidermidis (D)
FVNSLIMKDLSDNDMRFKYEYYNREK
1147


M. luteus (A)
DT



MRSA (R)




C. jeikeium (D)





PF-076
S. epidermidis (S)
LYQYELLSKEEYLKCTLIINQRRNEQK
1148


M. luteus (A)




MRSA (R)




C. jeikeium (A)





PF-099
S. epidermidis (D)
EIIAYLEGRFANA
1149


C. jeikeium (C)





PF-123
S. epidermidis (M)
TTRPQVAEDRQLDDALKETFPASDPISP
1150



PF-124
S. epidermidis (C)
MADGQIAAIAKLHGVPVATRNIRHFQS
1151


C. jeikeium (R)
FGVELINPWSG




PF-125
S. epidermidis (D)
YVVGALVILAVAGLIYSMLRKA
1152


M. luteus (C)





PF-127
S. epidermidis (M)
MLRYLSLFAVGLATGYAWGWIDGLA
1153


M. luteus (A)
ASLAV



C. jeikeium (A)





PF-128
S. epidermidis (D)
GIKVVAARFEEIQFSENFDSIILA
1154


P. aeruginosa (C)





PF-129
S. epidermidis (M)
MKLLARDPWVCAWNDIW
1155


C. jeikeium (R)





PF-133
C. jeikeium (R)
GDPTAGQKPVECP
1156



PF-135
C. jeikeium (R)
PPARPARIPQTPTLHGASLFRQRS
1157



PF-137
S. epidermidis (D)
VLGKGHDLLDVGKTALKSRVFAWLG
1158


M. luteus (D)
GS



C. jeikeium (A)





PF-139
S. epidermidis (M)
ALSKPAIQARTLCRRQDPP
1159


M. luteus (C)




C. jeikeium (R)





PF-140
S. epidermidis (D)
FHRRVIRASEWALTTRSFSTPLRSAAR
1160


M. luteus (R)




P. aeruginosa (A)




C. albicans (B)




MRSA (M)




S. pneumoniae (D)




C. jeikeium (D)




C. jejuni (D)





PF-143
P. aeruginosa (C)
LSPRPIIVSRRSRADNNNDWSR
1161



PF-144
S. pneumoniae (H)
RSGQPVGRPSRRAWLR
1162



PF-145
S. epidermidis (D)
GIVLTGRAGLVSGACSMALGVGLG
1163


M. luteus (A)




B. subtilis (C)




MRSA (M)




S. pneumoniae (R)




C. jeikeium (R)




C. jejuni (R)





PF-148
S. epidermidis (D)
RRGCTERLRRMARRNAWDLYAEHFY
1164


M. luteus (A)




B. subtilis (I)




C. albicans (B)




MRSA (C)




S. pneumoniae (R)




C. jeikeium (H)




C. jejuni (H)





PF-149
MRSA (H)
GKVSVLTRVPRSLGGAPANQ
1165



PF-153
S. epidermidis (M)
GILARADCSQIA
1166


C. jeikeium (C)





PF-156
MRSA (H)
LITAEQPATAPIAGK
1167



PF-157
S. epidermidis (M)
HTAVVWLAGVSGCVALSHCEPA
1168



PF-164
C. jeikeium (R)
EEVSRALAGIGLGLGCRIG
1169



PF-168
P. aeruginosa (H)
VLPFPAIPLSRRRACVAAPRPRSRQRAS
1170


MRSA (I)





PF-171
S. epidermidis (R)
TQVTLCRTW
1171


M. luteus (R)




B. subtilis (D)




MRSA (M)




S. pneumoniae (D)




C. jejuni (R)





PF-173
S. epidermidis (A)
AGRTAIVQGGG
1172


C. jeikeium (D)





PF-175
M. luteus (S)
RRRPAGQRPEKASQAMIAA
1173


B. subtilis (D)




C. albicans (B)




S. pneumoniae (A)




C. jejuni (M)





PF-176
S. epidermidis (C)
RLTSNQFLTRITPFVFAQH
1174


M. luteus (C)




C. jeikeium (D)





PF-178
S. epidermidis (D)
EVYSSPTNNVAITVQNN
1175


E. coli (C)




MRSA (M)




S. pneumoniae (D)





PF-180
S. epidermidis (C)
SGLGDLGFSSEAK
1176



PF-186
S. epidermidis (C)
DADKNLSLERDRFAWRVAAP
1177


C. jeikeium (A)





PF-188
C. jeikeium (H)
ARTFAGRLGTRYFGGLMRSTKA
1178



PF-190
S. epidermidis (C)
HFILRKPLLFMIHSLKTGPLDRF
1179


C. jeikeium (R)





PF-191
S. epidermidis (A)
QFCNFAWLFLASNNAQVSALA
1180


MRSA (H)




C. jeikeium (R)





PF-192
S. epidermidis (D)
VEEDEAPPPHY
1181



PF-196
S. epidermidis (C)
TTARYIRRQCHTSITPLSQG
1182


C. jeikeium (R)





PF-199
S. epidermidis (C)
FPAFSFGAIAGSVSVAR
1183


M. luteus (A)




C. jeikeium (R)





PF-203
S. epidermidis (A)
SWKCHHLAI
1184


C. jeikeium (R)





PF-204
S. epidermidis (C)
ALQKQDMNLPSVKNQLVFLKSTG
1185


M. luteus (C)




P. aeruginosa (H)




C. jeikeium (D)





PF-208
S. epidermidis (D)
DAYHCHLVRSPDAHDLSMRIGFV
1186


C. jeikeium (A)





PF-209
S. epidermidis (C)
NYAVVSHT
1187


P. aeruginosa (H)




MRSA (I)





PF-212
M. luteus (M)
NDSKASN
1188



PF-215
M. luteus (T)
ELKITNYNVNTVLYRYYKWGNDLCE
1189



PF-220
S. pneumoniae (H)
VDPADDGTRHIRPEDGDPIEIDE
1190



PF-224
M. luteus (T)
DYFYITLSQKNTF
1191



PF-226
S. epidermidis (C)
LMFFSENMDKRDTLSGKFRYFAGSKVI
1192


M. luteus (T)
KLMNWLSENGK




PF-233
S. epidermidis (C)
DANAMARTTIAIVYILALIALTISYSL
1193



PF-234
M. luteus (T)
RTPYILRS
1194



PF-235
M. luteus (T)
GIPFSKPHKRQVNYMKSDVLAYIEQNK
1195



MAHTA




PF-249
M. luteus (R)
INSRYKISF
1196



PF-250
M. luteus (T)
SEDIFGRLANEKANGLEELRKIRLKQ
1197



PF-255
M. luteus (M)
DHKINESQHNPFRSDSNKQNVDFF
1198



PF-257
M. luteus (R)
VWENRKKYLENEIERHNVFLKLGQEVI
1199



KGLNALASRGR




PF-264
M. luteus (H)
MQSLSNRQSLIASYILMGIFLSFGYPPA
1200



SLSKFFCRLSHL




PF-270
M. luteus (H)
MYLTPYAWIAVGSIFAFSVTTIKIGDQN
1201



DEKQKSHKNDVHKR




PF-271
M. luteus (T)
AAQPQTTSP
1202



PF-273
S. epidermidis (C)
LVGALLIFVALIYMVLKGNADKN
1203



PF-274
M. luteus (M)
SIQEAEKIIKNDPFYIHDVADYDFMWF
1204



EPSKSLEEIKEFV




PF-276
M. luteus (M)
LDLALSTNSLNLEGFSF
1205



PF-278
S. epidermidis (I)
LSLATFAKIFMTRSNWSLKRFNRL
1206


M. luteus (R)




C. albicans (B)





PF-283
S. epidermidis (H)
MIRIRSPTKKKLNRNSISDWKSNTSGRF
1207


B. subtilis (H)
FY




PF-289
B. subtilis (C)
MGRHLWNPSYFVATVSENTEEQIRKY
1208



RKNK




PF-290
S. epidermidis (C)
MVHDMTNGTLIIVKH
1209



PF-292
S. epidermidis (C)
SFVSTTVRLIFEESKRYKF
1210


B. subtilis (C)





PF-293
S. epidermidis (C)
YDPLK
1211



PF-294
S. epidermidis (C)
DFLVNFLWFKGELNWGKKRYK
1212



PF-296
S. epidermidis (C)
GAFGMPSIKTNTICGEKGKFISACDAW
1213


B. subtilis (C)
LSNLK




PF-297
S. epidermidis (C)
ISKGIDDIVYVINKILSIGNIFKIIKRK
1214


B. subtilis (C)





PF-301
S. epidermidis (C)
GIVLIGLKLIPLLANVLN
1215


B. subtilis (C)





PF-303
B. subtilis (C)
EYPWSWISEPWPWDKSFYK
1216



PF-305
B. subtilis (C)
MREWICPSCNETHDRDINASINILKEGL
1217



RLITIQNK




PF-306
B. subtilis (C)
GCILPHKKDNYNYIMSKFQDLVKITSK
1218



K




PF-307
S. epidermidis (T)
MKRRRCNWCGKLFYLEEKSKEAYCC
1219


B. subtilis (H)
KECRKKAKKVKK



C. albicans (B)





PF-310
S. epidermidis (C)
GVALIGTILVPLLSGLFG
1220



PF-313
S. epidermidis (C)
YITSHKNARAIIKKFERDEILEEVITHYL
1221



NRK




PF-318
S. epidermidis (C)
MGRHLWNPSYFVATVSENTEEQIRKYI
1222


B. subtilis (C)
NNQKKQVK




PF-319
S. epidermidis (C)
SIGSMIGMYSFRHKTKHIKFTFGIPFILF
1223


B. subtilis (C)
LQFLLVYFYILK




PF-322
S. epidermidis (C)
GIVLIGLKLIPLLANVLR
1224


B. subtilis (H)





PF-335
S. epidermidis (C)
AAYPIEDWSDWYEDFFIMLSNI
1225


B. subtilis (C)





PF-339
S. epidermidis (C)
KKIDILINKYMYLSK
1226


B. subtilis (C)





PF-342
S. epidermidis (C)
AFSGVYKTLIVYTRRK
1227


B. subtilis (C)





PF-344
E. coli (A)
DERLPEAKAIRNFNGSVMVLGR
1228



PF-347
S. epidermidis (C)
GIFTGVTVVVSLKHC
1229


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-349
S. epidermidis (C)
MPKSCHVPVLCDFFFLVIIKFLALFKTI
1230


E. coli (C)
QS



MRSA (C)




E. faecalis (C)





PF-350
S. epidermidis (C)
LAVILRAIVY
1231


E. coli (C)




MRSA (C)





PF-354
MRSA (H)
FTFSKCRASNGRGFGTLWL
1232



PF-355
S. epidermidis (C)
WIAIGLLLYFSLKNQ
1233


E. coli (C)




P. aeruginosa (A)




MRSA (A)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-356
S. epidermidis (S)
VSIKIGAIVIGMIGLMELLTE
1234


P. aeruginosa (A)




MRSA (C)




S. pneumoniae (R)




E. faecalis (R)




C. jejuni (D)





PF-357
S. epidermidis (M)
MLTIIIGFIFWTMTLMLGYLIGEREGRK
1235


M. luteus (C)
RE



MRSA (M)




S. pneumoniae (M)





PF-360
S. epidermidis (S)
MEQKVKVIFVPRSKPDNQLKTFVSAVL
1236


E. coli (C)
FKA



MRSA (H)





PF-362
E. coli (C)
NIERILKEKVWMIRCVE
1237


MRSA (C)





PF-363
S. epidermidis (S)
SMLSVTVMCLMHASVAANQAMEKKV
1238


E. coli (C)




MRSA (H)




S. pneumoniae (R)




E. faecalis (D)




C. jejuni (D)





PF-366
S. epidermidis (R)
ALCSVIKAIELGIINVHLQ
1239


E. coli (C)




P. aeruginosa (A)




MRSA (D)




S. pneumoniae (C)




E. faecalis (C)




C. jejuni (D)





PF-369
S. epidermidis (S)
MSEAVNLLRGARYSQRYAKNQVPYEV
1240


E. coli (R)
IIEK



MRSA (H)




E. faecalis (C)





PF-370
S. epidermidis (C)
VIFLHKESGNLKEIFY
1241


E. coli (R)




MRSA (C)





PF-373
S. epidermidis (M)
HFYLLFER
1242


MRSA (M)





PF-374
S. epidermidis (C)
HLFFVKGMFILCQKNQINDE
1243


E. coli (C)




MRSA (M)




E. faecalis (C)





PF-375
S. epidermidis (C)
MDSAKAQTMRTDWLAVSCLVASAYL
1244


E. coli (C)
RSMLA



MRSA (C)




E. faecalis (C)





PF-376
S. epidermidis (C)
MTVFEALMLAIAFATLIVKISNKNDKK
1245


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-378
S. epidermidis (M)
ESAKSNLNFLMQEEWALFLLL
1246


MRSA (M)





PF-379
S. epidermidis (C)
VFVVLFIIYLASKLLTKLFPIKK
1247


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-380
S. epidermidis (C)
KKIIPLITLFVVTLVG
1248


E. coli (C)




P. aeruginosa (A)




MRSA (D)




S. pneumoniae (D)




E. faecalis (C)




C. jejuni (D)





PF-381
S. epidermidis (C)
QGANPCQQVGFTVNDPDCRLAKTV
1249


E. coli (R)




MRSA (C)




E. faecalis (C)





PF-382
MRSA (M)
KYKCSWCKRVYTLRKDHKTAR
1250



PF-383
S. epidermidis (C)
WSEIEINTKQSN
1251


E. coli (R)





PF-385
E. coli (A)
MIKKSILKIKYYVPVLISLTLILSA
1252



PF-386
S. epidermidis (C)
FTLTLITTIVAILNYKDKKK
1253


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-387
S. epidermidis (C)
GAVGIAFFAGNMKQDKRIADRQNKKS
1254


E. coli (M)
EKK



MRSA (C)




E. faecalis (C)





PF-389
S. epidermidis (R)
GLQFKEIAEEFHITTTALQQWHKDNGY
1255


MRSA (C)
PIYNKNNRK



S. pneumoniae (D)




E. faecalis (R)




C. jejuni (R)





PF-390
S. epidermidis (D)
VVAYVITQVGAIRF
1256


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-392
MRSA (S)
DPAGCNDIVRKYCK
1257


E. faecalis (A)




C. jejuni (A)





PF-393
S. epidermidis (R)
DLVQSILSEFKKSG
1258


MRSA (C)




S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-394
MRSA (C)
VLKEECYQKN
1259


E. faecalis (A)





PF-395
S. epidermidis (C)
YCVPLGNMGNMNNKIW
1260


E. coli (R)




MRSA (C)





PF-396
S. epidermidis (S)
LIYTILASLGVLTVLQAILGREPKAVKA
1261


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-397
S. epidermidis (C)
VEDLMEDLNA
1262



PF-398
S. epidermidis (C)
ILVVLAGILLVVLSYVGISKFKMNC
1263


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-399
S. epidermidis (C)
FPIISALLGAIICIAIYSFIVNRKA
1264


E. coli (C)




MRSA (C)




E. faecalis (C)





PF-401
S. epidermidis (C)
YWLSRVTTGHSFAFEKPVPLSLTIK
1265


E. coli (R)




MRSA (C)




E. faecalis (C)





PF-403
S. epidermidis (M)
LLSTEQLLKYYDGETFDGFQLPSNE
1266


E. coli (R)




MRSA (M)





PF-404
S. epidermidis (M)
VLYFQATVV
1267


MRSA (M)





PF-405
MRSA (M)
LVRIEVDDLEEWYERNFI
1268



PF-406
S. epidermidis (C)
YLEMNADYLSNMDIFDELWEKYLENN
1269


MRSA (M)
K




PF-407
S. epidermidis (M)
KPKNKKEKTVISYEKLLSMY
1270


MRSA (C)




S. pneumoniae (R)




E. faecalis (R)





PF-408
S. epidermidis (M)
YCVPLGNMGNMNNKIW
1271


MRSA (M)





PF-410
S. epidermidis (C)
FALELIALCRNLFIVYFP
1272


E. coli (S)




MRSA (M)




E. faecalis (C)





PF-411
S. epidermidis (C)
WVAVAILLNIALQTQLT
1273


E. coli (C)




P. aeruginosa (A)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-413
S. epidermidis (C)
TFAGSIKIGVPDLVHVTFNCKR
1274


E. coli (S)




MRSA (C)





PF-414
S. pneumoniae (H)
LLNKKLE
1275



PF-415
S. pneumoniae (D)
MIDVTIGQKSKTGAFNASYSICFSGENF
1276



SF




PF-416
S. pneumoniae (H)
SKAGLYGKIERSDKRE
1277



PF-417
S. epidermidis (M)
DSYFRS
1278


MRSA (M)




S. pneumoniae (M)





PF-418
S. epidermidis (M)
FFLVHFYIRKRKGKVSIFLNYF
1279


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-419
S. pneumoniae (H)
VVTGKVGSLPQIK
1280



PF-421
S. pneumoniae (H)
KHCFEITDKTDVV
1281



PF-422
S. epidermidis (R)
MSRKKYENDEKSQKKLKIGRKSDVFY
1282


MRSA (C)
GIID



S. pneumoniae (C)




E. faecalis (R)




C. jejuni (R)





PF-423
S. pneumoniae (H)
AGKKERLLSFREQFLNKNKKK
1283



PF-424
S. pneumoniae (H)
IAAFVTSRAFSDTVSPI
1284



PF-425
S. epidermidis (D)
MMELVLKTIIGPIVVGVVLRIVDKWLN
1285


E. coli (C)
KDK



P. aeruginosa (A)




C. albicans (A)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-426
S. epidermidis (D)
MLQKYTQMISVTKCIITKNKKTQENVD
1286


E. coli (C)
AYN



C. albicans (A)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-427
E. coli (C)
YVLEYHGLRATQDVDAFMAL
1287


MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-428
S. pneumoniae (H)
ENEESIF
1288



PF-429
S. epidermidis (C)
AATLICVGSGIMSSL
1289


MRSA (C)




S. pneumoniae (M)




E. faecalis (C)





PF-430
S. epidermidis (M)
AVVCGYLAYTATS
1290


MRSA (M)




S. pneumoniae (M)





PF-431
S. epidermidis (M)
VAYAAICWW
1291


MRSA (C)




S. pneumoniae (R)




E. faecalis (R)




C. jejuni (R)





PF-432
S. epidermidis (M)
FNGDSEFFLCIAF
1292


E. coli (R)




P. aeruginosa (A)




MRSA (M)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-433
S. pneumoniae (H)
MRKEFHNVLSSGQLLADKRPARDYNR
1293



K




PF-434
S. pneumoniae (S)
GQLLADKRPARDYNRK
1294



PF-437
S. pneumoniae (I)
FQKPFTGEEVEDFQDDDEIPTII
1295



PF-439
S. epidermidis (C)
RVLVLKKFHGIMDGNRNVAVFFVGQ
1296


E. coli (R)




MRSA (M)




S. pneumoniae (R)




E. faecalis (C)





PF-440
S. epidermidis (C)
MFIISPDLFNIAVILYILFFIHDILLLILS
1297


E. coli (R)




MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-442
MRSA (M)
MQIFYIKTKIFLSFFLFLLIFSQCFYKIEE
1298


S. pneumoniae (C)





PF-443
E. coli (R)
KLLYFFNYFENLQQVHLLVQL
1299


MRSA (C)




S. pneumoniae (C)





PF-444
S. epidermidis (C)
MAAKLWEEGKMVYASSASMTKRLKL
1300


E. coli (R)
AMSKV



MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-445
S. pneumoniae (M)
ASMTKRLKLAMSKV
1301



PF-446
S. pneumoniae (H)
SGNEKV
1302



PF-447
S. epidermidis (C)
IDKSRNKDQFSHIFGLYNICSG
1303


MRSA (C)




S. pneumoniae (C)




E. faecalis (C)





PF-448
S. pneumoniae (I)
SLQSQLGPCLHDQRH
1304



PF-449
S. pneumoniae (H)
MPTTKSKQKGWTNTKKASNTQ
1305



PF-450
MRSA (C)
HRNLIILQRTIFI
1306


S. pneumoniae (C)




E. faecalis (C)





PF-451
S. epidermidis (C)
MVNYIIGSYMLYREQNNNEALRKFDIT
1307


E. coli (R)
LAM



MRSA (C)




S. pneumoniae (C)




E. faecalis (C)





PF-452
S. epidermidis (C)
MNNWIKVAQISVTVINEVIDIMKEKQN
1308


E. coli (C)
GGK



MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-453
S. epidermidis (C)
IIQDIAHAFGY
1309


E. coli (C)




MRSA (C)




S. pneumoniae (C)





PF-454
S. epidermidis (C)
MSVFVPVTNIFMFIMSPIFNVNLLHFKV
1310


E. coli (R)
YI



P. aeruginosa (H)




MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-455
S. pneumoniae (A)
MARNDDDIKKIKGTLGQSPEVYGERK
1311



LPYT




PF-456
E. faecalis (A)
TCVKPRTIN
1312


C. jejuni (A)





PF-457
S. pneumoniae (M)
INKYHHIA
1313



PF-458
P. aeruginosa (H)
ISLIIFIMLFVVALFKCITNYKHQS
1314


MRSA (M)




S. pneumoniae (M)





PF-459
S. pneumoniae (H)
EKRMSFNENQSHRPLL
1315



PF-460
S. epidermidis (C)
MEHVLPFQNTPPNIVIIYKDFTHLKSITF
1316


E. coli (H)
S



MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-461
MRSA (R)
MTLAIKNCSVTKCLGFGDFVNDDSDS
1317


S. pneumoniae (R)
YFDA



E. faecalis (A)





PF-462
S. pneumoniae (H)
KNKTDTL
1318



PF-464
S. pneumoniae (S)
VDMVNRFLGN
1319



PF-465
S. pneumoniae (H)
KPVGKALEEIADGKIEPVVPKEYLG
1320



PF-466
S. pneumoniae (H)
VRKSDQ
1321



PF-467
S. pneumoniae (H)
YYKDYFKEI
1322



PF-468
S. pneumoniae (H)
EDNKDKKDKKDK
1323



PF-469
S. epidermidis (D)
YKVNYNNIDNHFNTLRH
1324


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-470
E. faecalis (A)
PYSDSYATRPHWEQHRAR
1325


C. jejuni (A)





PF-471
S. epidermidis (C)
MVGKIRGVTPRNDLLNANITGQLNLN
1326


E. coli (C)
YRLI



P. aeruginosa (A)




MRSA (D)




S. pneumoniae (D)




E. faecalis (C)




C. jejuni (D)





PF-472
MRSA (C)
MHISHLLDEVEQTEREKAVNVLENMN
1327


S. pneumoniae (R)
GNVI



E. faecalis (A)




C. jejuni (R)





PF-473
S. epidermidis (R)
MAADIISTIGDLVKWIIDTVNKFKK
1328


E. coli (C)




MRSA (C)




S. pneumoniae (H)




E. faecalis (R)




C. jejuni (R)





PF-474
S. epidermidis (C)
MHRNLVLVKMEPIPHIMIIANQIGIIIEK
1329


E. coli (C)
A



P. aeruginosa (A)




C. albicans (B)




MRSA (D)




S. pneumoniae (D)




E. faecalis (C)




C. jejuni (D)





PF-475
S. epidermidis (M)
MREKVRFTQAFKLFWTNYFNFKGRSR
1330


C. albicans (B)
RSEY



MRSA (S)




S. pneumoniae (R)




E. faecalis (R)




C. jejuni (R)





PF-476
S. pneumoniae (H)
WADAQYKLCENCSE
1331



PF-477
S. pneumoniae (H)
HKNKLNIPHIKS
1332



PF-478
S. epidermidis (C)
HLFILKSHLKPFPPFRYTYD
1333


E. coli (C)




MRSA (H)




S. pneumoniae (C)





PF-479
S. pneumoniae (C)
AYILKRREEKNK
1334



PF-480
S. epidermidis (C)
MVEILVNTAISVYIVALYTQWLSTRDN
1335


E. coli (R)
LKA



MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-482
S. pneumoniae (S)
LVGYVRTSGTVRSYKIN
1336



PF-484
E. faecalis (A)
HKKDIRKQVFKN
1337



PF-485
S. pneumoniae (A)
KNSMSRSIALID
1338



PF-511
S. pneumoniae (H)
VMQ SLYVKPPLILVTKLAQQN
1339



PF-512
S. pneumoniae (H)
SFMPEIQKNTIPTQMK
1340



PF-513
S. pneumoniae (M)
SNGVGLGVGIGSGIRF-NH2
1341



PF-514
S. epidermidis (C)
QRFYKLFYHIDLTNEQALKLFQVK
1342


E. coli (R)




S. pneumoniae (M)




E. faecalis (C)





PF-515
S. pneumoniae (H)
DKSTQDKDIKQAKLLAQELGL-NH2
1343



PF-516
S. pneumoniae (H)
ASKQASKQASKQASKQ
1344



PF-517
S. pneumoniae (M)
VKPTMTASLISTVC
1345



PF-518
S. epidermidis (C)
SFYSKYSRYIDNLAGAIFLFF
1346


E. coli (R)




MRSA (C)




S. pneumoniae (M)




E. faecalis (C)





PF-519
E. coli (R)
YLVYSGVLATAAAF-NH2
1347


MRSA (C)




S. pneumoniae (S)




E. faecalis (C)





PF-520
S. pneumoniae (M)
LGLTAGVAYAAQPTNQPTNQPTNQPT
1348



NQPTNQPTNQPRW-NH2




PF-521
S. pneumoniae (H)
CGKLLEQKNFFLKTR
1349



PF-522
S. pneumoniae (H)
FELVDWLETNLGKILKSKSA-NH2
1350



PF-524
E. coli (M)
PDAPRTCYHKPILAALSRIVVTDR
1351


MRSA (C)




S. pneumoniae (M)




E. faecalis (C)





PF-525
S. pneumoniae (H)
KFSDQIDKGQDALKDKLGDL
1352



PF-526
S. epidermidis (C)
VLLLFIFQPFQKQLL-NH2
1353


E. coli (R)




C. albicans (C)




MRSA (C)




S. pneumoniae (R)





PF-527
S. epidermidis (M)
GSVIKKRRKRMAKKKHRKLLKKTRIQ
1354


M. luteus (S)
RRRAGK



B. subtilis (I)




P. aeruginosa (I)




C. albicans (B)




MRSA (I)




S. pneumoniae (H)




C. jeikeium (I)




C. jejuni (M)





PF-528
S. epidermidis (H)
LVDVVVLIRRHLPKSCS-NH2
1355


E. coli (H)




C. albicans (C)




MRSA (H)




S. pneumoniae (R)





PF-529
S. pneumoniae (H)
LSEMERRRLRKRA-NH2
1356



PF-530
S. epidermidis (H)
SKFKVLRKIIIKEYKGELMLSIQKQR
1357


E. coli (R)




MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-531
S. epidermidis (I)
YIQFHLNQQPRPKVKKIKIFL-NH2
1358


E. coli (M)




P. aeruginosa (I)




S. pneumoniae (C)





PF-532
E. coli (C)
KFIYKYKLSFIIYKILIQTLTMELNK
1359


MRSA (C)




S. pneumoniae (C)




E. faecalis (C)





PF-533
S. epidermidis (H)
KTPNDKIHKTIIIKHIIL
1360


E. coli (R)




MRSA (H)




S. pneumoniae (C)




E. faecalis (C)





PF-534
S. epidermidis (C)
KYFHLFYHNIIHYSKQHLSLKVDFKN-
1361


E. coli (R)
NH2



MRSA (C)




S. pneumoniae (R)




E. faecalis (C)





PF-535
P. aeruginosa (H)
NIKTRKRALKIIKQHQRSK
1362


S. pneumoniae (H)





PF-536
S. epidermidis (C)
MEPIPHIMIIANQIGIIIEKA
1363


E. coli (R)




P. aeruginosa (H)




MRSA (C)




S. pneumoniae (M)




E. faecalis (C)





PF-537
S. pneumoniae (C)
LANDYYKKTKKSW
1364



PF-538
S. pneumoniae (H)
KNKKQTDILEKVKEILDKKKKTKVG
1365



QKLY




PF-539
MRSA (H)
SIITKKKRRKIPLSIDSQIYKYTFKQ
1366


S. pneumoniae (A)





PF-540
S. epidermidis (H)
KSILILIKVIFIGQTTIIL
1367


E. coli (R)




MRSA (H)




S. pneumoniae (R)





PF-541
E. coli (H)
RRNLNSPNIKTRKRALKIIKQHQRSK
1368


S. pneumoniae (H)





PF-542
S. pneumoniae (H)
KKDNPSLNDQDKNAVLNLLALAK
1369



PF-543
S. mutans (S)
NILFGIIGFVVAMTAAVIVTAISIAK
1370


S. epidermidis (D)




M. luteus (C)




E. coli (C)




MRSA (D)




S. pneumoniae (D)





PF-544
S. epidermidis (D)
FGEKQMRSWWKVHWFHP
1371


MRSA (D)




S. pneumoniae (M)




E. faecalis (R)





PF-545
B. subtilis (I)
RESKLIAMADMIRRRI-NH2
1372


C. albicans (B)




E. faecalis (H)




C. jeikeium (H)





PF-546
S. epidermidis (D)
PIIAPTIKTQIQ
1373


E. coli (R)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jeikeium (D)





PF-547
S. epidermidis (R)
WSRVPGHSDTGWKVWHRW-NH2
1374


B. subtilis (I)




MRSA (M)




E. faecalis (R)





PF-548
S. epidermidis (M)
ARPIADLIHFNSTTVTASGDVYYGPG
1375


M. luteus (A)




B. subtilis (C)




MRSA (M)




S. pneumoniae (D)




C. jeikeium (R)




C. jejuni (D)





PF-549
B. subtilis (D)
TGIGPIARPIEHGLDS
1376


MRSA (C)





PF-550
B. subtilis (D)
STENGWQEFESYADVGVDPRRYVPL
1377



PF-551
MRSA (C)
QVKEKRREIELQFRDAEKKLEASVQAE
1378



PF-552
B. subtilis (D)
ELDKADAALGPAKNLAPLDVINRS
1379



PF-553
B. subtilis (D)
LTIVGNALQQKNQKLLLNQKKITSLG
1380


MRSA (M)




S. pneumoniae (R)




C. jeikeium (R)





PF-554
B. subtilis (D)
AKNFLTRTAEEIGEQAVREGNINGP
1381



PF-555
MRSA (M)
EAYMRFLDREMEGLTAAYNVKLFTEA
1382


S. pneumoniae (R)
IS



C. jejuni (R)





PF-556
S. epidermidis (A)
SLQIRMNTLTAAKASIEAA
1383


M. luteus (A)




B. subtilis (C)




MRSA (M)




S. pneumoniae (D)




E. faecalis (A)




C. jeikeium (D)




C. jejuni (R)





PF-557
B. subtilis (D)
AANKAREQAAAEAKRKAEEQAR
1384



PF-558
S. epidermidis (M)
ADAPPPLIVRYS
1385


B. subtilis (D)




MRSA (C)




S. pneumoniae (R)




C. jejuni (H)





PF-559
B. subtilis (C)
SRPGKPGGVSIDVSRDRQDILSNYP
1386


C. jejuni (A)





PF-560
B. subtilis (D)
FGNPFRGFTLAMEADFKKRK
1387


MRSA (C)




S. pneumoniae (R)




C. jejuni (A)





PF-561
B. subtilis (D)
ESLEADVQAELDTEAAKYPALPASF
1388


MRSA (M)





PF-562
S. epidermidis (A)
TPEQWLERSTVVVTGLLNRK
1389


M. luteus (R)




MRSA (M)




S. pneumoniae (D)




C. jejuni (R)





PF-563
B. subtilis (D)
RPELDNELDVVQNSASLDKLQASYN
1390


S. pneumoniae (H)




C. jejuni (H)





PF-564
B. subtilis (D)
TIILNDQINSLQERLNKLNAETDRR
1391


MRSA (C)




C. jeikeium (R)




C. jejuni (R)





PF-565
B. subtilis (D)
RAEAEAQRQAEADAKRKAEEAARL
1392


MRSA (C)





PF-566
M. luteus (D)
EAQQVTQQLGADFNAITTPTATKV
1393


B. subtilis (C)




MRSA (M)




S. pneumoniae (D)




C. jeikeium (C)




C. jejuni (D)





PF-567
M. luteus (C)
QQRVKAVDASLSQVSTQVSGAVASA
1394


MRSA (D)




S. pneumoniae (D)




C. jeikeium (C)




C. jejuni (D)





PF-569
B. subtilis (D)
KSKISEYTEKEFLEFVEDIYTNNK
1395



PF-571
B. subtilis (D)
SDLLYYPNENREDSPAGVVKEVKE
1396



PF-572
B. subtilis (D)
WRASKGLPGFKAG
1397


S. pneumoniae (R)





PF-573
S. pneumoniae (C)
EKKLIVKLIDSIGKSHEEIVGAG
1398



PF-574
B. subtilis (D)
LVKSGKLESPYEHSEHLTLSQEKGLE
1399



PF-575
P. aeruginosa (A)
LNFRAENKILEKIHISLIDTVEGSA
1400


S. pneumoniae (A)




C. jeikeium (A)




C. jejuni (R)





PF-576
S. epidermidis (A)
AYSGELPEPLVRKMSKEQVRSVMGK
1401


E. coli (A)




MRSA (R)




S. pneumoniae (C)




C. jejuni (C)





PF-577
S. epidermidis (A)
PFETRESFRVPVIGILGGWDYFMHP
1402


E. coli (A)




P. aeruginosa (A)




MRSA (M)




S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-578
S. mutans (D)
QKANLRIGFTYTSDSNVCNLTFALLGS
1403


S. epidermidis (D)
K



M. luteus (C)




P. mirabilis (C)




E. coli (C)




MRSA (C)




S. pneumoniae (D)





PF-580
S. epidermidis (M)
EILNNNQVIKELTMKYKTQFESNLGG
1404


M. luteus (C)
WTARARR



MRSA (M)




S. pneumoniae (C)





PF-581
MRSA (A)
WTARARR
1405


S. pneumoniae (A)




E. faecalis (A)




C. jejuni (A)





PF-582
E. faecalis (A)
NLKTIEKECPFCNNKMDIKLKD
1406



PF-583
S. mutans (F)
KFQGEFTNIGQSYIVSASHMSTSLNTG
1407


S. epidermidis (I)
K



MRSA (I)




S. pneumoniae (D)





PF-584
S. epidermidis (C)
SYIKNLSNQKFLIAF
1408


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-585
S. epidermidis (S)
DYNHLLNVVQDWVNTN
1409


MRSA (S)




S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-586
S. epidermidis (C)
FFNQANYFFKEF
1410


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-587
S. pneumoniae (C)
ASGKYQSYLLNVYVDSKKDRLDIFDK
1411



LKAKAKFVL




PF-588
E. faecalis (A)
ESVEAIKAKAIK
1412



PF-589
MRSA (M)
APLRIDEIRNSNVIDEVLDCAPKKQEHF
1413


S. pneumoniae (C)
FVVPKIIE




PF-590
C. jejuni (R)
YYQAKLFPLL
1414



PF-591
S. pneumoniae (R)
DLLKSLLGQDGAKNDEIIEFIKIIMEK
1415


E. faecalis (A)




C. jejuni (C)





PF-592
S. epidermidis (M)
IMKNYKYFKLFIVKYALF
1416


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (S)





PF-593
E. faecalis (A)
MEISTLKKEKLHVKDELSQYLANYKK
1417



PF-594
E. faecalis (C)
IVSAIV
1418



PF-595
S. epidermidis (C)
LQNKIYELLYIKERSKLCS
1419


E. coli (C)




MRSA (D)




S. pneumoniae (R)




E. faecalis (D)




C. jejuni (D)





PF-596
S. epidermidis (D)
SKMWDKILTILILILELIRELIKL
1420


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-597
E. faecalis (A)
DEIKVSDEEIEKFIKENNL
1421



PF-598
S. epidermidis (R)
MKFMLEVRNKAISAYKEITRTQI
1422


E. coli (C)




MRSA (D)




S. pneumoniae (R)




E. faecalis (R)




C. jejuni (R)





PF-599
S. epidermidis (M)
LFEIFKPKH
1423


MRSA (C)




S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-600
S. mutans (S)
TKKIELKRFVDAFVKKSYENYILEREL
1424


S. epidermidis (C)
KKLIKAINEELPTK



M. luteus (C)




E. coli (H)




MRSA (M)




S. pneumoniae (R)





PF-601
E. faecalis (A)
YRVTVKALE
1425


C. jejuni (A)





PF-602
E. faecalis (A)
LEKEKKEYIEKLFKTK
1426



PF-603
S. epidermidis (D)
IDKLKKMNLQKLSYEVRISQDGKSIYA
1427


M. luteus (A)
RIK



E. coli (M)




MRSA (M)




S. pneumoniae (C)





PF-604
E. faecalis (A)
LMEQVEV
1428



PF-605
S. epidermidis (R)
HYRWNTQWWKY
1429


E. coli (C)




P. aeruginosa (A)




C. albicans (B)




MRSA (C)




S. pneumoniae (D)




E. faecalis (R)




C. jejuni (R)





PF-606
S. mutans (I)
FESKILNASKELDKEKKVNTALSFNSH
1430


S. epidermidis (I)
QDFAKAYQNGKI



C. albicans (B)




MRSA (I)




S. pneumoniae (H)





PF-607
S. epidermidis (M)
YIESDPRKFDYIFGAIRDH
1431


MRSA (S)




S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-609
MRSA (C)
TEIKLDNNEYLVLNLDDILGILK
1432


S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-610
S. epidermidis (C)
VFLKLKTSKIDLASIIFYP
1433


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-612
S. mutans (F)
GTTLKYGLERQLKIDIHPEITIINLNGGA
1434


S. epidermidis (C)
DEFAKL



M. luteus (A)




P. mirabilis (C)




E. coli (C)




MRSA (C)




S. pneumoniae (C)





PF-613
S. epidermidis (R)
ADEFAKL
1435


MRSA (C)




E. faecalis (A)





PF-614
S. epidermidis (M)
GLDIYA
1436


S. pneumoniae (R)




E. faecalis (A)




C. jejuni (R)





PF-615
S. epidermidis (D)
FLNRFIFYIFTVKTKSALIKNLFLD
1437


E. coli (C)




MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jejuni (D)





PF-616
S. epidermidis (R)
IVFVVTKEKK
1438


E. faecalis (A)





PF-617
C. albicans (H)
PMNAAEPE
1439


S. pneumoniae (I)




E. faecalis (H)





PF-618
S. pneumoniae (I)
KLNTLNKKDNPSLNDQDKNAVLNLLA
1440


E. faecalis (H)
LAK




PF-619
S. epidermidis (M)
WSRVPGHSDTGWKVWHRW
1441


E. coli (C)




MRSA (M)




S. pneumoniae (C)





PF-621
S. pneumoniae (I)
PPSSFLV
1442


E. faecalis (H)





PF-622
S. epidermidis (D)
TREDVFSVRLINNIVNKQA
1443


MRSA (D)




S. pneumoniae (M)




E. faecalis (D)




C. jeikeium (D)





PF-623
S. epidermidis (M)
VLFAVYLGALDWLFSWLTQKM
1444


MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jeikeium (R)





PF-624
S. mutans (D)
VFLLDSYCFVKINL
1445


S. epidermidis (D)




M. luteus (C)




P. mirabilis (C)




E. coli (C)




MRSA (C)




S. pneumoniae (D)





PF-625
S. pneumoniae (H)
SDSTNNARTRKKARDVTTKDIDK
1446



PF-626
S. pneumoniae (H)
KYDFDDFEPEEA
1447



PF-627
S. epidermidis (H)
INDLLSYFTLHEK
1448


C. albicans (B)




MRSA (R)




S. pneumoniae (I)




E. faecalis (H)





PF-629
S. epidermidis (C)
GLAAIATVFALY
1449


MRSA (D)




S. pneumoniae (M)




E. faecalis (R)




C. jeikeium (R)





PF-630
MRSA (M)
IPATPIIHS
1450



PF-631
S. pneumoniae (I)
LIIYFSKTGNTARATRQI
1451


E. faecalis (H)





PF-632
S. epidermidis (D)
TTIQGVASLEKHGFRYTITYPTRI
1452


B. subtilis (H)




C. albicans (B)




MRSA (D)




S. pneumoniae (M)




E. faecalis (D)




C. jeikeium (D)





PF-634
S. mutans (D)
MPKARPVNHNKKKSKITIKSNFTLFYM
1453


S. epidermidis (D)
FNP



M. luteus (C)




P. mirabilis (C)




E. coli (C)




MRSA (D)




S. pneumoniae (D)





PF-635
S. epidermidis (M)
MNAHGHSLIFQKMIVHAFAFFSKQKN
1454


C. albicans (B)
YLYF



MRSA (D)




S. pneumoniae (D)




E. faecalis (D)




C. jeikeium (D)





PF-636
B. subtilis (H)
LVRLA
1455


C. albicans (B)




S. pneumoniae (H)




E. faecalis (H)





PF-637
S. epidermidis (M)
SRIKQDARSVRKYDRIGIFFYSFKSA
1456


MRSA (M)




S. pneumoniae (M)




E. faecalis (D)




C. jeikeium (D)





PF-638
S. epidermidis (R)
TFILPK
1457


MRSA (M)




S. pneumoniae (I)




E. faecalis (H)





PF-639
C. albicans (B)
QATQIKSWIDRLLVSED
1458


MRSA (R)




S. pneumoniae (I)




E. faecalis (H)





PF-640
C. albicans (B)
MGDINRNF
1459


S. pneumoniae (I)




E. faecalis (H)





PF-642
MRSA (M)
FTTPMIGIPAGLLGGSYYLKRREEKGK
1460



PF-643
MRSA (C)
VRCRL
1461


S. pneumoniae (R)




E. faecalis (R)





PF-644
S. pneumoniae (H)
TSGLIIGENGLNGL
1462



PF-645
C. albicans (B)
SNSVQQG
1463


S. pneumoniae (I)





PF-646
C. albicans (B)
APASPGRRPG
1464


S. pneumoniae (H)





PF-647
C. albicans (B)
GTFLGQKCAAATAS
1465


S. pneumoniae (R)





PF-649
E. faecalis (R)
CPRYPFVDVGPAGPWRARWRVGS
1466



PF-651
S. pneumoniae (H)
PRWPTGAGRHR
1467



PF-652
S. pneumoniae (A)
FLAPARPDLQAQRQALAQ
1468



PF-653
S. pneumoniae (H)
QSVHPLPAETPVADVI
1469



PF-654
C. albicans (B)
LSGRLAGRR
1470


MRSA (R)




S. pneumoniae (A)





PF-655
S. epidermidis (R)
DAPCFDDQFGDLKCQMC
1471


B. subtilis (H)




MRSA (M)




S. pneumoniae (H)





PF-656
MRSA (R)
RGMFVPFHDVDCVQ
1472



PF-657
S. epidermidis (C)
YVANYTITQFGRDFDDRLAVAIHFA
1473


MRSA (D)




S. pneumoniae (H)




E. faecalis (D)




C. jeikeium (D)





PF-658
MRSA (R)
PTTPPPTTPPEIPTGGTVIST
1474


S. pneumoniae (H)





PF-659
S. epidermidis (M)
TVIST
1475


B. subtilis (H)




MRSA (R)




S. pneumoniae (C)





PF-660
S. pneumoniae (H)
TDPQATAAPRRRTSPR
1476



PF-661
MRSA (R)
PDEDIRRRAILPPAGPCRPMSPE
1477



PF-662
S. pneumoniae (A)
GKQSRAHGPVASRREFRRKSG
1478



PF-663
S. pneumoniae (A)
ATLIPRKA
1479



PF-664
S. epidermidis (M)
DQLCVEYPARVSTG
1480


MRSA (R)




S. pneumoniae (M)




E. faecalis (R)





PF-665
S. pneumoniae (H)
VLRVATAVGEVPTGL
1481



PF-666
S. pneumoniae (A)
PNRRSRPR
1482



PF-667
S. epidermidis (R)
PAHQRLRIDQRLVADRDMVQDYES
1483


MRSA (R)




S. pneumoniae (R)




E. faecalis (R)





PF-668
S. epidermidis (M)
TNAESMALAFRGRVHMSVNIAGLT
1484


B. subtilis (A)




C. albicans (A)




MRSA (R)




S. pneumoniae (M)




E. faecalis (D)




C. jeikeium (D)





PF-670
B. subtilis (H)
TVIVAPMHSGV
1485


S. pneumoniae (H)





PF-672
S. epidermidis (I)
MRFGSLALVAYDSAIKHSWPRPSSVRR
1486


B. subtilis (I)
LRM



C. albicans (I)




MRSA (I)




S. pneumoniae (I)




E. faecalis (I)




C. jeikeium (R)





PF-675
S. pneumoniae (C)
EIIPISPTRRCEMHTMSSAEYRGL
1487


E. faecalis (R)





PF-677
S. epidermidis (R)
TCRGAGMH
1488


MRSA (D)




S. pneumoniae (D)




E. faecalis (R)





PF-680
MRSA (R)
ADPHPTTGI
1489



PF-681
S. epidermidis (M)
TALTTVGVSGARLITYCVGVEDI
1490


MRSA (M)




S. pneumoniae (M)




E. faecalis (R)




C. jeikeium (R)





PF-682
S. pneumoniae (A)
RRGKSEQGLSRR
1491



PF-683
S. epidermidis (R)
LWPVA
1492


MRSA (R)




S. pneumoniae (H)





PF-684
C. albicans (B)
RKLSLASGFALWRRSLV
1493


S. pneumoniae (C)




E. faecalis (A)





PF-685
S. epidermidis (M)
PTLWLACL
1494


MRSA (M)




S. pneumoniae (M)




E. faecalis (R)




C. jeikeium (R)





PF-686
S. epidermidis (H)
LAVLMGYIGYRGWSGKRHINRQ
1495


B. subtilis (I)




C. albicans (B)




MRSA (M)




S. pneumoniae (A)




E. faecalis (R)





PF-687
S. pneumoniae (A)
AKRVLSLAVAPHRRQPVQGT
1496



PF-688
S. pneumoniae (A)
ARNHAVIPAG
1497



PF-690
S. epidermidis (R)
MIPLAGDPVSSHRTVEFGVLGTYLVSG
1498


MRSA (R)
GSL



S. pneumoniae (M)




E. faecalis (R)





PF-691
S. pneumoniae (R)
HRTVEFGVLGTYLVSGGSL
1499



PF-692
MRSA (R)
GVAREDPLEPDPLAPIIDDSR
1500



PF-693
S. pneumoniae (A)
PDPAR
1501



PF-694
MRSA (R)
DLIRPLYSMSAPSVA
1502


S. pneumoniae (A)





PF-695
MRSA (R)
ALSVMLGNIPLVVPNANQL
1503


S. pneumoniae (C)




E. faecalis (R)





PF-696
S. pneumoniae (H)
IRSGISAAYARPLR
1504



PF-697
C. albicans (H)
RADARAK
1505


S. pneumoniae (H)





PF-698
C. albicans (H)
SSGRAGVKCRRPTGR
1506


S. pneumoniae (A)




E. faecalis (A)





PF-699
S. pneumoniae (A)
GRAGVKCRRPTGR
1507



PF-700
S. pneumoniae (C)
LNWPFTGR
1508



PF-702
S. pneumoniae (H)
LSGRLAGRR
1509



PF-704
S. pneumoniae (C)
APAARAAL
1510



PF-737
S. pneumoniae (D)
KSSGSSASASSTAGGSSSK
1511



PF-738
MRSA (M)
KSGATSAASGAKSGASS
1512



PF-741
S. mutans (D)
AKREDTVAAQIGANILNLIQ
1513


S. epidermidis (C)




M. luteus (C)




P. mirabilis (C)




E. coli (C)




MRSA (C)




S. pneumoniae (D)





PF-744
S. pneumoniae (H)
LGVGTFVGKVLIKNQQKQKSKKKAQ
1514



PF-745
S. mutans (D)
ANSQNSLFSNRSSFKSIFDKKSNITTNA
1515


M. luteus (C)
TTPNSNIIIN



MRSA (C)




S. pneumoniae (C)





PF-746
S. mutans (D)
FLGNSQYFTRK
1516


S. epidermidis (C)




M. luteus (C)




E. coli (C)




P. aeruginosa (A)




MRSA (C)




S. pneumoniae (C)





PF-748
S. pneumoniae (H)
FQGFFDVAVNKWWEEHNKAKLWKN
1517



VKGKFLEGEGEEEDDE




PF-749
S. pneumoniae (H)
GVNKWWEEHNKAKLWKNVKGKFLE
1518



GEGEEEDDE




PF-752
S. pneumoniae (C)
LHVIRPRPELSELKFPITKILKVNKQGL
1519



KK




PF-756
S. pneumoniae (A)
DALLRLA
1520



PF-757
S. pneumoniae (H)
PQAISSVQQNA
1521



PF-760
S. epidermidis (M)
DHITLDDYEIHDGFNFELYYG
1522


MRSA (M)




S. pneumoniae (C)





PF-761
S. mutans (D)
SKFELVNYASGCSCGADCKCASETECK
1523


S. epidermidis (C)
CASKK



M. luteus (C)




E. coli (C)




P. aeruginosa (C)




MRSA (D)




S. pneumoniae (C)





PF-762
S. pneumoniae (H)
PAPAPSAPAPAPEQPEQPA
1524



PF-763
S. epidermidis (M)
GIWMARNYFHRSSIRKVYVESDKEYE
1525


M. luteus (C)
RVHPMQKIQYEGNYKSQ



MRSA (D)




S. pneumoniae (C)





PF-764
MRSA (D)
GYFEPGKRD
1526


S. pneumoniae (H)





PF-770
S. mutans (D)
GVGIGFIMMGVVGYAVKLVHIPIRYLI
1527


S. epidermidis (D)
V



M. luteus (C)




P. mirabilis (C)




E. coli (C)




MRSA (D)




S. pneumoniae (C)





PF-776
S. mutans (D)
VSILLYLSATIILPNVLRLLVARAIIVRV
1528


S. epidermidis (D)




M. luteus (C)




E. coli (C)




MRSA (D)




S. pneumoniae (C)





PF-C052
P. gingivalis (H)
SRFRNGV
1529



PF-C055
F. nucleatum (T)
YNLSIYIYFLHTITIAGLITLPFII
1530


S. mutans (I)





PF-C057
S. mutans (I)
YFWWYWVQDCIPYKNNEVWLELSNN
1531



MK




PF-C058
S. mutans (F)
FETGFGDGYYMSLWGLNEKDEVCKV
1532



VIPFINPELID




PF-C061
F. nucleatum (T)
TLNYKKMFFSVIFLLGLNYLICNSPLFF
1533


S. mutans (F)
KQIEF




PF-C062
F. nucleatum (T)
PLARATEVVATLFIICSLLLYLTR
1534


S. mutans (I)





PF-C064
F. nucleatum (T)
DEEALEMGANLYAQFAIDFLNSKK
1535



PF-C065
F. nucleatum (T)
DEERYSDSYFLKEKVFYLILALFLILFH
1536



QKYLYFLEIITI




PF-C069
F. nucleatum (T)
NALMLREMQLAKNIKVEVTDVLSNKK
1537



YC




PF-C071
F. nucleatum (T)
QVIVKIL
1538



PF-C072
F. nucleatum (T)
KKMFSLIRKVNWIFFILFIVLDLTNVFP
1539


P. gingivalis (T)
LIRTILFAILSRQ



S. mutans (F)





PF-C075
F. nucleatum (T)
KALVISVFAIVFSIIFVKFFYWRDKK
1540


P. gingivalis (R)




S. mutans (F)





PF-C084
F. nucleatum (T)
FFSVIFLFGLNYLICNSPLFNILR
1541


P. gingivalis (R)




S. mutans (F)





PF-C085
S. mutans (F)
KKFKIFVIINWFYHKYIILNFEENF
1542



PF-C086
F. nucleatum (T)
ELFFTILSDCNELFLLHLLQQPLFYIKK
1543



GK




PF-C088
F. nucleatum (H)
DIANNILNSVSERLIIA
1544


P. gingivalis (R)




S. mutans (I)





PF-C089
P. gingivalis (R)
MPKRHYYKLEAKALQFGLPFAYSPIQL
1545



LK




PF-C091
F. nucleatum (T)
ASNTPRFVRLTLFNFYSKIWNVTHLFLF
1546



NNL




PF-C095
F. nucleatum (T)
LLALNMNEDTYYFELFFIFDNQNKKW
1547



LIFDLKERG




PF-C098
F. nucleatum (T)
PETKGKVSAFVFGIVVANVIAVVYILY
1548


S. mutans (F)
MLREIGIIQ




PF-C120
F. nucleatum (T)
ASLSTMTFKVMELKELIILLCGLTMLMI
1549



QTEFV




PF-C131
F. nucleatum (T)
QWIVAKREIRMHIYCHISVIHVIIFFG
1550


S. mutans (F)





PF-C135
F. nucleatum (C)
KNTHAYLRVLRLSSLILSYQASVYPLF
1551


S. mutans (F)
AYLCQQKDY




PF-C136
F. nucleatum (C)
LILSYQASVYPLFAYLCQQKDY
1552


P. gingivalis (R)





PF-C 137
F. nucleatum (T)
QRMYWFKRGFETGDFSAGDTFAELK
1553



PF-C 139
S. mutans (F)
LLASHPERLSLGVFFVYRVLHLLLENT
1554



PF-C 142
S. mutans (I)
DFPPLSFFRRRFHAYTAPIDNFFGANPF
1555



PF-C 143
F. nucleatum (C)
VVFGGGDRLV
1556



PF-C 145
F. nucleatum (C)
YGKESDP
1557


S. mutans (I)





PF-C180
P. gingivalis (R)
TVEELDKAFTWGAAAALAIGVIAINVG
1558


S. mutans (S)
LAAGYCYNNNDVF




PF-C181
F. nucleatum (T)
KMRAGQVVFIYKLILVLLFYVLQKLFD
1559



LKKGCF




PF-C194
F. nucleatum (T)
NTNDLLQAFELMGLGMAGVFIVLGILY
1560


P. gingivalis (T)
IVAELLIKIFPVNN



S. mutans (F)





PF-C214
F. nucleatum (T)
GGHKQLVIEPLVSQ
1561



PF-C281
S. mutans (F)
KKEKLLTAIRLQHRAEIRGYFTIFFLFFR
1562



I




PF-C290
S. mutans (F)
GNVHPESDFHNLIQFIKTFLYFTIFFKYF
1563



L




PF-C291
F. nucleatum (T)
HPFLTGTGCPLFLIFRLFFVKAYFSFTVF
1564


S. mutans (F)





PF-C293
F. nucleatum (T)
IIIILPKIYLVCKTV
1565


P. gingivalis (R)




S. mutans (F)





PF-S003
S. epidermidis (R)
ALALLKQDLLNFEGRGRIITSTYLQFNE
1566


M. luteus (R)
GCVP



B. subtilis (A)




P. aeruginosa (A)




C. albicans (A)




MRSA (M)




S. pneumoniae (D)




C. jeikeium (D)




C. jejuni (D)



Key to Abbreviations: (A) Peptide aggregates; (B) Less hyphal formation; (C) Clumps; (D) Diffuse clumps and small polyps; (F) Diffuse growth; (H) Thin; (I) Growth inhibition; (M) Microcolony formation; (R) Rippled; (S) Small polyps; (T) Thick; (W) Halo formation on top, microlonies on bottom. These data thus indicate peptide-mediated interruption of bacterial biofilm formation processes, cellular metabolism, cellular import/export, nutrient acquisition, quorum sensing and communication, motility, chemotaxis, replication, translation, and/or transcription. Accordingly, without being bound to a particular theory, it is believed that the alteration of one or more of these basic pathways is important to pathogenesis, or the stopping thereof














































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































In certain embodiments, the amino acid sequence of the antimicrobial peptides comprises or consists of a single amino acid sequence, e.g., as listed above in Tables 4 and/or 5, and/or Table 15, and/or below in Table 14. In certain embodiments the amino acid sequence of the antimicrobial peptides comprises two copies, three copies, four copies, five copies six copies or more of one or more of the amino acid sequences listed in Tables 4, and/or 5, and/or Table 15, and/or Table 14. Thus, compound antimicrobial constructs are contemplated where the construct comprises multiple domains each having antimicrobial activity. The AMP domains comprising such a construct can be the same or different. In certain embodiments the construct comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 different AMP domains each domain comprising a different AMP sequence.
Various AMP domains comprising such a construct can be joined directly to each other or two or more of such domains can be attached to each other via a linker. An illustrative, but non-limiting, list of suitable linkers is provided in Table 16. Thus, in certain embodiments, two or more AMP domains comprising a compound AMP construct are chemically conjugated together.
In certain embodiments the two or more AMP domains comprising the AMP construct are joined by a peptide linker. Where all the AMP domains are attached directly to each other or are joined by peptide linkers, the entire construct can be provided as a single-chain peptide (fusion protein).
In various embodiments, the antimicrobial peptides described herein comprise one or more of the amino acid sequences shown in Tables 4, and/or 5, and/or 15 and/or 14 (and/or the retro, inverso, retroinverso, etc. forms of such sequences). In certain embodiments the peptides range in length up to about 100 amino acids in length, preferably up to about 80, about 70, about 60, or about 51 amino acids in length. In certain embodiments the peptides range in length from about 8 amino acids up to about 100 amino acids 80 amino acids, 60 amino acids or about 51 amino acids in length. In certain embodiments the peptides range in length from about 8 up to about 50, 40, 30, 20, 15, 15, 13, or 12 amino acids in length.
As shown in Tables 4, and/or 5, and/or 15 and/or 14, the various amino acid sequences described herein are effective against particular microorganisms. The range of activity of the peptides or compositions comprising such peptides can be increased by including amino acid sequences effective against different microorganisms either as separate components and/or as multiple domains within a single construct.





TABLE 6



Illustrative target microorganisms and peptides effective against that target.



Gram Positive Bacteria:





A. naeslundii

PF-531, PF-527, PF-672, PF-545, PF-168, PF-448, PF-525, PF-529, PF-


148


B. subtilis

PF-002, PF-005, PF-006, PF-040, PF-053, PF-056, PF-061, PF-063, PF-


067, PF-068, PF-069, PF-070, PF-071, PF-145, PF-148, PF-171, PF-175,


PF-283, PF-289, PF-292, PF-296, PF-297, PF-301, PF-303, PF-305, PF-


306, PF-307, PF-318, PF-319, PF-322, PF-335, PF-339, PF-342, PF-497,


PF-499, PF-527, PF-531, PF-545, PF-547, PF-548, PF-549, PF-550, PF-


552, PF-553, PF-554, PF-556, PF-557, PF-558, PF-559, PF-560, PF-561,


PF-563, PF-564, PF-565, PF-566, PF-569, PF-571, PF-572, PF-574, PF-


632, PF-636, PF-655, PF-659, PF-668, PF-670, PF-672, PF-686, PF-998,


PF-2003


C. difficile

PF-522, PF-531, PF-538


C. jeikeium

PF-001, PF-003, PF-004, PF-101, PF-011, PF-012, PF-013, PF-021, PF-


022, PF-025, PF-028, PF-030, PF-032, PF-033, PF-036, PF-037, PF-040,


PF-042, PF-043, PF-046, PF-048, PF-052, PF-053, PF-056, PF-057, PF-


063, PF-065, PF-067, PF-068, PF-073, PF-075, PF-076, PF-099, PF-124,


PF-127, PF-129, PF-133, PF-135, PF-137, PF-139, PF-140, PF-145, PF-


148, PF-164, PF-173, PF-176, PF-186, PF-188, PF-190, PF-191, PF-196,


PF-199, PF-203, PF-204, PF-208, PF-527, PF-531, PF-545, PF-546, PF-


548, PF-553, PF-556, PF-564, PF-566, PF-567, PF-575, PF-622, PF-523,


PF-629, PF-632, PF-635, PF-637, PF-657, PF-668, PF-672, PF-681, PF-


685, PF-S003


E. faecalis

PF-007, PF-053, PF-057, PF-068, PF-347, PF-349, PF-355, PF-356, PF-


363, PF-366, PF-369, PF-374, PF-375, PF-376, PF-379, PF-380, PF-381,


PF-386, PF-387, PF-389, PF-390, PF-392, PF-393, PF-394, PF-396, PF-


398, PF-399, PF-401, PF-407, PF-410, PF-411, PF-418, PF-422, PF-425,


PF-426, PF-427, PF-429, PF-431, PF-432, PF-439, PF-440, PF-444, PF-


447, PF-450, PF-451, PF-452, PF-454, PF-456, PF-460, PF-461, PF-469,


PF-470, PF-471, PF-472, PF-473, PF-474, PF-475, PF-480, PF-484, PF-


514, PF-518, PF-519, PF-524, PF-530, PF-532, PF-533, PF-534, PF-536,


PF-544, PF-545, PF-546, PF-547, PF-556, PF-577, PF-581, PF-582, PF-


584, PF-585, PF-586, PF-588, PF-591, PF-592, PF-593, PF-594, PF-595,


PF-596, PF-597, PF-598, PF-599, PF-601, PF-602, PF-604, PF-605, PF-


607, PF-609, PF-610, PF-613, PF-614, PF-615, PF-616, PF-617, PF-618,


PF-621, PF-622, PF-623, PF-627, PF-629, PF-631, PF-632, PF-635, PF-


636, PF-637, PF-638, PF-639, PF-640, PF-643, PF-649, PF-657, PF-664,


PF-667, PF-668, PF-672, PF-675, PF-677, PF-681, PF-684, PF-685, PF-


686, PF-690, PF-695, PF-698


M. luteus

PF-001, PF-003, PF-004, PF-006, PF-007, PF-010, PF-012, PF-013, PF-


020, PF-021, PF-022, PF-025, PF-030, PF-036, PF-037, PF-040, PF-042,


PF-043, PF-051, PF-052, PF-053, PF-056, PF-057, PF-063, PF-067, PF-


068, PF-071, PF-073, PF-075, PF-076, PF-125, PF-127, PF-137, PF-139,


PF-140, PF-145, PF-148, PF-171, PF-175, PF-176, PF-199, PF-204, PF-


212, PF-215, PF-224, PF-226, PF-234, PF-235, PF-249, PF-250, PF-255,


PF-257, PF-264, PF-270, PF-271, PF-274, PF-276, PF-278, PF-357, PF-


527, PF-543, PF-548, PF-556, PF-562, PF-566, PF-567, PF-578, PF-580,


PF-600, PF-603, PF-612, PF-624, PF-634, PF-741, PF-745, PF-746, PF-


761, PF-763, PF-770, PF-776, PF-S003

MRSA
PF-001, PF-003, PF-004, PF-006, PF-007, PF-010, PF-011, PF-012, PF-


013, PF-015, PF-017, PF-019, PF-020, PF-021, PF-022, PF-023, PF-024,


PF-025, PF-026, PF-027, PF-028, PF-029, PF-030, PF-031, PF-033, PF-


035, PF-036, PF-037, PF-040, PF-041, PF-042, PF-043, PF-045, PF-046,


PF-048, PF-049, PF-051, PF-052, PF-053, PF-056, PF-057, PF-058, PF-


063, PF-064, PF-065, PF-066, PF-067, PF-068, PF-071, PF-073, PF-074,


PF-075, PF-076, PF-140, PF-145, PF-148, PF-149, PF-156, PF-168, PF-


171, PF-178, PF-191, PF-209, PF-347, PF-349, PF-350, PF-354, PF-355,


PF-356, PF-357, PF-360, PF-362, PF-366, PF-369, PF-370, PF-373, PF-


374, PF-375, PF-376, PF-378, PF-379, PF-380, PF-381, PF-382, PF-386,


PF-387, PF-389, PF-390, PF-392, PF-393, PF-394, PF-395, PF-396, PF-


398, PF-399, PF-401, PF-403, PF-404, PF-405, PF-406, PF-407, PF-408,


PF-410, PF-411, PF-413, PF-417, PF-418, PF-422, PF-425, PF-426, PF-


427, PF-429, PF-430, PF-431, PF-432, PF-439, PF-440, PF-442, PF-443,


PF-444, PF-447, PF-450, PF-451, PF-452, PF-453, PF-454, PF-458, PF-


460, PF-461, PF-469, PF-471, PF-472, PF-473, PF-474, PF-475, PF-478,


PF-480, PF-518, PF-519, PF-524, PF-526, PF-527, PF-528, PF-530, PF-


532, PF-533, PF-534, PF-536, PF-539, PF-540, PF-543, PF-544, PF-545,


PF-546, PF-547, PF-548, PF-549, PF-551, PF-553, PF-555, PF-556, PF-


558, PF-560, PF-561, PF-562, PF-564, PF-565, PF-566, PF-567, PF-576,


PF-577, PF-578, PF-580, PF-581, PF-583, PF-584, PF-585, PF-586, PF-


589, PF-592, PF-595, PF-596, PF-598, PF-599, PF-600, PF-603, PF-605,


PF-606, PF-607, PF-609, PF-610, PF-612, PF-613, PF-615, PF-619, PF-


622, PF-623, PF-624, PF-627, PF-629, PF-630, PF-632, PF-634, PF-635,


PF-637, PF-638, PF-639, PF-652, PF-643, PF-654, PF-655, PF-656, PF-


657, PF-658, PF-659, PF-661, PF-664, PF-667, PF-778, PF-672, PF-677,


PF-680, PF-683, PF-685, PF-686, PF-690, PF-692, PF-694, PF-695, PF-


738, PF-741, PF-745, PF-746, PF-760, PF-761, PF-763, PF-764, PF-770,


PF-776, PF-S003


S. epidermidis

PF-001, PF-003, PF-004, PF-006, PF-007, PF-009, PF-010, PF-012, PF-


013, PF-020, PF-021, PF-022, PF-024, PF-025, PF-027, PF-028, PF-030,


PF-032, PF-033, PF-034, PF-036, PF-037, PF-040, PF-041, PF-042, PF-


043, PF-046, PF-048, PF-051, PF-052, PF-953, PF-956, PF-957, PF-961,


PF-963, PF-964, PF-965, PF-967, PF-968, PF-971, PF-073, PF-074, PF-


075, PF-076, PF-099, PF-123, PF-124, PF-125, PF-127, PF-128, PF-129,


PF-137, PF-139, PF-140, PF-145, PF-148, PF-153, PF-157, PF-171, PF-


173, PF-176, PF-178, PF-180, PF-186, PF-190, PF-191, PF-192, PF-196,


PF-199, PF-203, PF-204, PF-208, PF-209, PF-226, PF-233, PF-273, PF-


278, PF-283, PF-290, PF-292, PF-293, PF-294, PF-296, PF-297, PF-301,


PF-307, PF-310, PF-313, PF-318, PF-319, PF-322, PF-335, PF-339, PF-


342, PF-347, PF-349, PF-350, PF-355, PF-356, PF-357, PF-360, PF-363,


PF-366, PF-369, PF-370, PF-373, PF-374, PF-375, PF-376, PF-378, PF-


379, PF-380, PF-381, PF-383, PF-386, PF-387, PF-389, PF-390, PF-393,


PF-395, PF-396, PF-397, PF-398, PF-399, PF-401, PF-403, PF-404, PF-


406, PF-407, PF-408, PF-410, PF-411, PF-413, PF-417, PF-418, PF-422,


PF-425, PF-246, PF-249, PF-430, PF-431, PF-432, PF-439, PF-440, PF-


444, PF-447, PF-451, PF-452, PF-453, PF-454, PF-460, PF-469, PF-471,


PF-473, PF-474, PF-475, PF-478, PF-480, PF-514, PF-518, PF-526, PF-


527, PF-528, PF-530, PF-531, PF-533, PF-534, PF-536, PF-540, PF-543,


PF-544, PF-546, PF-547, PF-548, PF-556, PF-558, PF-562, PF-576, PF-


577, PF-578, PF-580, PF-583, PF-584, PF-585, PF-586, PF-592, PF-595,


PF-596, PF-598, PF-599, PF-600, PF-603, PF-605, PF-606, PF-607, PF-


610, PF-612, PF-613, PF-614, PF-615, PF-616, PF-619, PF-622, PF-623,


PF-624, PF-627, PF-632, PF-634, PF-635, PF-637, PF-638, PF-655, PF-


657, PF-659, PF-664, PF-667, PF-778, PF-672, PF-677, PF-681, PF-683,


PF-685, PF-686, PF-690, PF-741, PF-746, PF-760, PF-761, PF-763, PF-


770, PF-776, PF-S003


S. mutans

G-1, G-2, G-4, G-8, PF-020, PF-040, PF-051, PF-531, PF-543, PF-547,


PF-578, PF-583, PF-600, PF-606, PF-612, PF-624, PF-634, PF-741, PF-


745, PF-746, PF-761, PF-770, PF-776, PF-C055, PF-C057, PF-C058, PF-


C061, PF-C062, PF-C072, PF-C075, PF-C084, PF-C085, PF-C088, PF-


C098, PF-C131, PF-C135, PF-C139, PF-C142, PF-C146, PF-C180, PF-


C194, PF-C281, PF-C290, PF-C291, PF-C293


S. pneumoniae

PF-002, PF-005, PF-006, PF-020, PF-033, PF-040, PF-051, PF-053, PF-


056, PF-057, PF-061, PF-063, PF-068, PF-071, PF-073, PF-140, PF-144,


PF-145, PF-148, PF-171, PF-175, PF-178, PF-220, PF-355, PF-356, PF-


357, PF-363, PF-366, PF-380, PF-389, PF-390, PF-393, PF-407, PF-411,


PF-414, PF-415, PF-416, PF-417, PF-418, PF-419, PF-421, PF-422, PF-


423, PF-424, PF-425, PF-426, PF-427, PF-428, PF-429, PF-430, PF-431,


PF-432, PF-433, PF-434, PF-437, PF-439, PF-440, PF-442, PF-443, PF-


444, PF-445, PF-446, PF-447, PF-448, PF-449, PF-450, PF-451, PF-452,


PF-453, PF-454, PF-455, PF-457, PF-458, PF-469, PF-460, PF-461, PF-


462, PF-464, PF-465, PF-466, PF-467, PF-468, PF-469, PF-471, PF-472,


PF-473, PF-474, PF-475, PF-476, PF-477, PF-478, PF-479, PF-480, PF-


482, PF-485, PF-511, PF-512, PF-513, PF-514, PF-515, PF-516, PF-517,


PF-518, PF-519, PF-520, PF-521, PF-522, PF-523, PF-524, PF-525, PF-


526, PF-527, PF-528, PF-529, PF-530, PF-531, PF-532, PF-533, PF-534,


PF-535, PF-536, PF-537, PF-538, PF-539, PF-540, PF-541, PF-542, PF-


543, PF-544, PF-546, PF-548, PF-553, PF-555, PF-556, PF-558, PF-560,


PF-562, PF-563, PF-566, PF-567, PF-572, PF-573, PF-575, PF-576, PF-


577, PF-578, PF-580, PF-581, PF-583, PF-585, PF-585, PF-586, PF-587,


PF-589, PF-591, PF-592, PF-595, PF-596, PF-598, PF-599, PF-600, PF-


603, PF-605, PF-606, PF-607, PF-609, PF-610, PF-612, PF-614, PF-615,


PF-617, PF-618, PF-619, PF-621, PF-622, PF-623, PF-624, PF-625, PF-


626, PF-627, PF-629, PF-631, PF-632, PF-634, PF-635, PF-636, PF-637,


PF-638, PF-639, PF-640, PF-643, PF-644, PF-645, PF-646, PF-647, PF-


651, PF-652, PF-653, PF-654, PF-655, PF-657, PF-658, PF-659, PF-660,


PF-662, PF-663, PF-664, PF-665, PF-666, PF-667, PF-668, PF-670, PF-


672, PF-675, PF-677, PF-681, PF-682, PF-683, PF-684, PF-685, PF-686,


PF-687, PF-688, PF-690, PF-691, PF-693, PF-694, PF-695, PF-696, PF-


697, PF-698, PF-699, PF-700, PF-702, PF-704, PF-737, PF-741, PF-744,


PF-745, PF-746, PF-748, PF-749, PF-752, PF-756, PF-757, PF-760, PF-


761, PF-762, PF-763, PF-764, PF-770, PF-776, PF-S003



Gram Negative Bacteria:





A. baumannii

PF-531, PF-006, PF-538, PF-530


C. jejuni

PF-006, PF-008, PF-033, PF-040, PF-053, PF-056, PF-057, PF-059, PF-


061, PF-063, PF-067, PF-068, PF-069, PF-071, PF-073, PF-140, PF-145,


PF-148, PF-171, PF-175, PF-355, PF-356, PF-363, PF-366, PF-380, PF-


389, PF-390, PF-392, PF-393, PF-411, PF-418, PF-422, PF-425, PF-426,


PF-431, PF-432, PF-456, PF-469, PF-470, PF-471, PF-472, PF-473, PF-


474, PF-475, PF-527, PF-548, PF-555, PF-556, PF-558, PF-559, PF-560,


PF-562, PF-563, PF-564, PF-566, PF-567, PF-575, PF-576, PF-577, PF-


581, PF-584, PF-585, PF-586, PF-590, PF-591, PF-592, PF-595, PF-596,


PF-598, PF-599, PF-601, PF-605, PF-607, PF-609, PF-610, PF-614, PF-


615, PF-S003


E. coli

PF-007, PF-040, PF-053, PF-057, PF-068, PF-178, PF-344, PF-347, PF-


349, PF-350, PF-355, PF-360, PF-362, PF-363, PF-366, PF-369, PF-370,


PF-374, PF-375, PF-376, PF-379, PF-380, PF-381, PF-383, PF-385, PF-


386, PF-387, PF-390, PF-395, PF-396, PF-398, PF-399, PF-401, PF-403,


PF-410, PF-411, PF-413, PF-418, PF-425, PF-426, PF-427, PF-432, PF-


439, PF-440, PF-443, PF-444, PF-451, PF-452, PF-453, PF-454, PF-460,


PF-469, PF-471, PF-473, PF-474, PF-478, PF-480, PF-514, PF-518, PF-


519, PF-524, PF-526, PF-528, PF-530, PF-531, PF-532, PF-533, PF-534,


PF-536, PF-540, PF-541, PF-543, PF-546, PF-576, PF-577, PF-578, PF-


584, PF-586, PF-592, PF-595, PF-596, PF-598, PF-600, PF-603, PF-605,


PF-606, PF-610, PF-612, PF-615, PF-619, PF-624, PF-634, PF-741, PF-


746, PF-761, PF-770, PF-776


F. nucleatum

PF-C055, PF-C061, PF-C062, PF-C064, PF-C065, PF-C069, PF-C071,


PF-C072, PF-C075, PF-C084, PF-C086, PF-C088, PF-C091, PF-C095,


PF-C098, PF-C120, PF-C131, PF-C135, PF-C136, PF-C137, PF-C143,


PF-C145, PF-C181, PF-C194, PF-C214, PF-C291, PF-C293


M. xanthus

G-5, G-6, G-7


P. aeruginosa

PF-053, PF-063, PF-067, PF-128, PF-140, PF-143, PF-168, PF-204, PF-


209, PF-355, PF-356, PF-366, PF-380, PF-411, PF-425, PF-432, PF-454,


PF-458, PF-471, PF-474, PF-527, PF-531, PF-535, PF-536, PF-575, PF-


577, PF-605, PF-746, PF-761, PF-S003


P. gingivalis

PF-C052, PF-C072, PF-C075, PF-C084, PF-C088, PF-C089, PF-C136,


PF-C180, PF-C194, C293


P. mirabilis

PF-040, PF-578, PF-612, PF-624, PF-634, PF-741, PF-770



Yeast Fungi:





A. niger

PF-531, PF-527, PF-672, PF-545, PF-168, PF-448, PF-525, PF-529, PF-


148


C. albicans

PF-053, PF-056, PF-057, PF-071, PF-140, PF-148, PF-175, PF-278, PF-


307, PF-425, PF-426, PF-474, PF-475, PF-526, PF-527, PF-528, PF-545,


PF-605, PF-606, PF-617, PF-627, PF-632, PF-635, PF-636, PF-639, PF-


640, PF-645, PF-646, PF-647, PF-654, PF-668, PF-672, PF-684, PF-686,


PF-697, PF-698, PF-S003


T. rubrum

PF-283, PF-307, PF-527, PF-531, PF-547, PF-672


























































































































































































































In certain embodiments the activity against a particular microorganism or group of microorganisms can be increased by increasing the number of peptides or peptide domains with activity against that microorganism or group of microorganisms.
Thus, for example, in certain embodiments, a peptide or composition effective to kill or inhibit the growth and/or proliferation of a yeast or fungus can comprise or more peptides and/or one or more peptide domains having sequences selected from the sequences shown in Tables 4, 5, or 6 (e.g., PF-S003, PF-053, PF-056, PF-057, PF-071, PF-140, PF-148, PF-168, PF-175, PF-278, PF-283, PF-307, PF-425, PF-426, PF-448, PF-474, PF-475, PF-525, PF-526, PF-527, PF-528, PF-529, PF-531, PF-545, PF-547, PF-606, PF-617, PF-627, PF-632, PF-635, PF-636, PF-639, PF-640, PF-645, PF-646, PF-647, PF-654, PF-668, PF-672, PF-684, PF-686, PF-697, and PF-69)8. A peptide or composition effective to kill or inhibit the growth and/or proliferation of Aspergillus niger can comprise one or more peptides and/or one or more peptide domains having sequences selected from the group consisting of PF-531, PF-527, PF-672, PF-545, PF-168, PF-448, PF-525, PF-529, and PF-148. A peptide or composition effective to kill or inhibit the growth and/or proliferation of Candida albicans can comprise one or more peptides and/or one or more peptide domains having sequences selected from the group consisting of PF-053, PF-056, PF-057, PF-071, PF-140, PF-148, PF-175, PF-278, PF-307, PF-425, PF-426, PF-474, PF-475, PF-526, PF-527, PF-528, PF-545, PF-605, PF-606, PF-617, PF-627, PF-632, PF-635, PF-636, PF-639, PF-640, PF-645, PF-646, PF-647, PF-654, PF-668, PF-672, PF-684, PF-686, PF-697, PF-698, and PF-S003. A peptide or composition effective to kill or inhibit the growth and/or proliferation of Trichophyton rubrum can comprise one or more peptides and/or one or more peptide domains having sequences selected from the group consisting of PF-283, PF-307, PF-527, PF-531, PF-547, and PF-672.
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of a bacterium can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against a bacterium in Tables 4, 5, or 6.
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of a gram positive bacterium can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against a gram positive bacterium in Tables 4, 5, or 6. In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of a gram negative bacterium can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against a gram negative bacterium in Tables 4, 5, or 6.
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of A. naeslundii can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against A. Naeslundii in Tables 4, 5, or 6 (e.g., from the group consisting of PF-531, PF-527, PF-672, PF-545, PF-168, PF-448, PF-525, PF-529, and PF-148).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of B. subtilis can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against B. subtilis in Tables 4, 5, or 6 (e.g., from the group consisting of PF-002, PF-005, PF-006, PF-040, PF-053, PF-056, PF-061, PF-063, PF-067, PF-068, PF-069, PF-070, PF-071, PF-145, PF-148, PF-171, PF-175, PF-283, PF-289, PF-292, PF-296, PF-297, PF-301, PF-303, PF-305, PF-306, PF-307, PF-318, PF-319, PF-322, PF-335, PF-339, PF-342, PF-497, PF-499, PF-527, PF-531, PF-545, PF-547, PF-548, PF-549, PF-550, PF-552, PF-553, PF-554, PF-556, PF-557, PF-558, PF-559, PF-560, PF-561, PF-563, PF-564, PF-565, PF-566, PF-569, PF-571, PF-572, PF-574, PF-632, PF-636, PF-655, PF-659, PF-668, PF-670, PF-672, PF-686, PF-998, and PF-2003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of C. difficile can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against C. difficile in Tables 4, 5, or 6 (e.g., from the group consisting of PF-522, PF-531, and PF-538).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of C. jeikeium can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against C. jeikeium in Tables 4, 5, or 6 (e.g., from the group consisting of PF-001, PF-003, PF-004, PF-101, PF-011, PF-012, PF-013, PF-021, PF-022, PF-025, PF-028, PF-030, PF-032, PF-033, PF-036, PF-037, PF-040, PF-042, PF-043, PF-046, PF-048, PF-052, PF-053, PF-056, PF-057, PF-063, PF-065, PF-067, PF-068, PF-073, PF-075, PF-076, PF-099, PF-124, PF-127, PF-129, PF-133, PF-135, PF-137, PF-139, PF-140, PF-145, PF-148, PF-164, PF-173, PF-176, PF-186, PF-188, PF-190, PF-191, PF-196, PF-199, PF-203, PF-204, PF-208, PF-527, PF-531, PF-545, PF-546, PF-548, PF-553, PF-556, PF-564, PF-566, PF-567, PF-575, PF-622, PF-523, PF-629, PF-632, PF-635, PF-637, PF-657, PF-668, PF-672, PF-681, PF-685, and PF-S003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of E. faecalis can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against E. faecalis in Tables 4, 5, or 6 (e.g., from the group consisting of PF-007, PF-053, PF-057, PF-068, PF-347, PF-349, PF-355, PF-356, PF-363, PF-366, PF-369, PF-374, PF-375, PF-376, PF-379, PF-380, PF-381, PF-386, PF-387, PF-389, PF-390, PF-392, PF-393, PF-394, PF-396, PF-398, PF-399, PF-401, PF-407, PF-410, PF-411, PF-418, PF-422, PF-425, PF-426, PF-427, PF-429, PF-431, PF-432, PF-439, PF-440, PF-444, PF-447, PF-450, PF-451, PF-452, PF-454, PF-456, PF-460, PF-461, PF-469, PF-470, PF-471, PF-472, PF-473, PF-474, PF-475, PF-480, PF-484, PF-514, PF-518, PF-519, PF-524, PF-530, PF-532, PF-533, PF-534, PF-536, PF-544, PF-545, PF-546, PF-547, PF-556, PF-577, PF-581, PF-582, PF-584, PF-585, PF-586, PF-588, PF-591, PF-592, PF-593, PF-594, PF-595, PF-596, PF-597, PF-598, PF-599, PF-601, PF-602, PF-604, PF-605, PF-607, PF-609, PF-610, PF-613, PF-614, PF-615, PF-616, PF-617, PF-618, PF-621, PF-622, PF-623, PF-627, PF-629, PF-631, PF-632, PF-635, PF-636, PF-637, PF-638, PF-639, PF-640, PF-643, PF-649, PF-657, PF-664, PF-667, PF-668, PF-672, PF-675, PF-677, PF-681, PF-684, PF-685, PF-686, PF-690, PF-695, and PF-698).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of M. luteus can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against M. luteus in Tables 4, 5, or 6 (e.g., from the group consisting of PF-001, PF-003, PF-004, PF-006, PF-007, PF-010, PF-012, PF-013, PF-020, PF-021, PF-022, PF-025, PF-030, PF-036, PF-037, PF-040, PF-042, PF-043, PF-051, PF-052, PF-053, PF-056, PF-057, PF-063, PF-067, PF-068, PF-071, PF-073, PF-075, PF-076, PF-125, PF-127, PF-137, PF-139, PF-140, PF-145, PF-148, PF-171, PF-175, PF-176, PF-199, PF-204, PF-212, PF-215, PF-224, PF-226, PF-234, PF-235, PF-249, PF-250, PF-255, PF-257, PF-264, PF-270, PF-271, PF-274, PF-276, PF-278, PF-357, PF-527, PF-543, PF-548, PF-556, PF-562, PF-566, PF-567, PF-578, PF-580, PF-600, PF-603, PF-612, PF-624, PF-634, PF-741, PF-745, PF-746, PF-761, PF-763, PF-770, PF-776, and PF-S003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of MRSA can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against MRSA in Tables 4, 5, or 6 (e.g., from the group consisting of PF-001, PF-003, PF-004, PF-006, PF-007, PF-010, PF-011, PF-012, PF-013, PF-015, PF-017, PF-019, PF-020, PF-021, PF-022, PF-023, PF-024, PF-025, PF-026, PF-027, PF-028, PF-029, PF-030, PF-031, PF-033, PF-035, PF-036, PF-037, PF-040, PF-041, PF-042, PF-043, PF-045, PF-046, PF-048, PF-049, PF-051, PF-052, PF-053, PF-056, PF-057, PF-058, PF-063, PF-064, PF-065, PF-066, PF-067, PF-068, PF-071, PF-073, PF-074, PF-075, PF-076, PF-140, PF-145, PF-148, PF-149, PF-156, PF-168, PF-171, PF-178, PF-191, PF-209, PF-347, PF-349, PF-350, PF-354, PF-355, PF-356, PF-357, PF-360, PF-362, PF-366, PF-369, PF-370, PF-373, PF-374, PF-375, PF-376, PF-378, PF-379, PF-380, PF-381, PF-382, PF-386, PF-387, PF-389, PF-390, PF-392, PF-393, PF-394, PF-395, PF-396, PF-398, PF-399, PF-401, PF-403, PF-404, PF-405, PF-406, PF-407, PF-408, PF-410, PF-411, PF-413, PF-417, PF-418, PF-422, PF-425, PF-426, PF-427, PF-429, PF-430, PF-431, PF-432, PF-439, PF-440, PF-442, PF-443, PF-444, PF-447, PF-450, PF-451, PF-452, PF-453, PF-454, PF-458, PF-460, PF-461, PF-469, PF-471, PF-472, PF-473, PF-474, PF-475, PF-478, PF-480, PF-518, PF-519, PF-524, PF-526, PF-527, PF-528, PF-530, PF-532, PF-533, PF-534, PF-536, PF-539, PF-540, PF-543, PF-544, PF-545, PF-546, PF-547, PF-548, PF-549, PF-551, PF-553, PF-555, PF-556, PF-558, PF-560, PF-561, PF-562, PF-564, PF-565, PF-566, PF-567, PF-576, PF-577, PF-578, PF-580, PF-581, PF-583, PF-584, PF-585, PF-586, PF-589, PF-592, PF-595, PF-596, PF-598, PF-599, PF-600, PF-603, PF-605, PF-606, PF-607, PF-609, PF-610, PF-612, PF-613, PF-615, PF-619, PF-622, PF-623, PF-624, PF-627, PF-629, PF-630, PF-632, PF-634, PF-635, PF-637, PF-638, PF-639, PF-652, PF-643, PF-654, PF-655, PF-656, PF-657, PF-658, PF-659, PF-661, PF-664, PF-667, PF-778, PF-672, PF-677, PF-680, PF-683, PF-685, PF-686, PF-690, PF-692, PF-694, PF-695, PF-738, PF-741, PF-745, PF-746, PF-760, PF-761, PF-763, PF-764, PF-770, PF-776, and PF-5003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of S. epidermidis can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against of S. epidermidis in Tables 4, 5, or 6 (e.g., from the group consisting of PF-001, PF-003, PF-004, PF-006, PF-007, PF-009, PF-010, PF-012, PF-013, PF-020, PF-021, PF-022, PF-024, PF-025, PF-027, PF-028, PF-030, PF-032, PF-033, PF-034, PF-036, PF-037, PF-040, PF-041, PF-042, PF-043, PF-046, PF-048, PF-051, PF-052, PF-953, PF-956, PF-957, PF-961, PF-963, PF-964, PF-965, PF-967, PF-968, PF-971, PF-073, PF-074, PF-075, PF-076, PF-099, PF-123, PF-124, PF-125, PF-127, PF-128, PF-129, PF-137, PF-139, PF-140, PF-145, PF-148, PF-153, PF-157, PF-171, PF-173, PF-176, PF-178, PF-180, PF-186, PF-190, PF-191, PF-192, PF-196, PF-199, PF-203, PF-204, PF-208, PF-209, PF-226, PF-233, PF-273, PF-278, PF-283, PF-290, PF-292, PF-293, PF-294, PF-296, PF-297, PF-301, PF-307, PF-310, PF-313, PF-318, PF-319, PF-322, PF-335, PF-339, PF-342, PF-347, PF-349, PF-350, PF-355, PF-356, PF-357, PF-360, PF-363, PF-366, PF-369, PF-370, PF-373, PF-374, PF-375, PF-376, PF-378, PF-379, PF-380, PF-381, PF-383, PF-386, PF-387, PF-389, PF-390, PF-393, PF-395, PF-396, PF-397, PF-398, PF-399, PF-401, PF-403, PF-404, PF-406, PF-407, PF-408, PF-410, PF-411, PF-413, PF-417, PF-418, PF-422, PF-425, PF-246, PF-249, PF-430, PF-431, PF-432, PF-439, PF-440, PF-444, PF-447, PF-451, PF-452, PF-453, PF-454, PF-460, PF-469, PF-471, PF-473, PF-474, PF-475, PF-478, PF-480, PF-514, PF-518, PF-526, PF-527, PF-528, PF-530, PF-531, PF-533, PF-534, PF-536, PF-540, PF-543, PF-544, PF-546, PF-547, PF-548, PF-556, PF-558, PF-562, PF-576, PF-577, PF-578, PF-580, PF-583, PF-584, PF-585, PF-586, PF-592, PF-595, PF-596, PF-598, PF-599, PF-600, PF-603, PF-605, PF-606, PF-607, PF-610, PF-612, PF-613, PF-614, PF-615, PF-616, PF-619, PF-622, PF-623, PF-624, PF-627, PF-632, PF-634, PF-635, PF-637, PF-638, PF-655, PF-657, PF-659, PF-664, PF-667, PF-778, PF-672, PF-677, PF-681, PF-683, PF-685, PF-686, PF-690, PF-741, PF-746, PF-760, PF-761, PF-763, PF-770, PF-776, and PF-S003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of S. mutans can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against S. mutans in Tables 4, 5, or 6 (e.g., from the group consisting of G-1, G-2, G-4, G-8, PF-020, PF-040, PF-051, PF-531, PF-543, PF-547, PF-578, PF-583, PF-600, PF-606, PF-612, PF-624, PF-634, PF-741, PF-745, PF-746, PF-761, PF-770, PF-776, PF-0055, PF-0057, PF-0058, PF-0061, PF-0062, PF-0072, PF-0075, PF-0084, PF-0085, PF-0088, PF-0098, PF-C131, PF-C135, PF-C139, PF-C142, PF-C146, PF-C180, PF-C194, PF-C281, PF-C290, PF-C291, PF-C293
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of S. pneumoniae can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against S. pneumoniae in Tables 4, 5, or 6 (e.g., from the group consisting of PF-002, PF-005, PF-006, PF-020, PF-033, PF-040, PF-051, PF-053, PF-056, PF-057, PF-061, PF-063, PF-068, PF-071, PF-073, PF-140, PF-144, PF-145, PF-148, PF-171, PF-175, PF-178, PF-220, PF-355, PF-356, PF-357, PF-363, PF-366, PF-380, PF-389, PF-390, PF-393, PF-407, PF-411, PF-414, PF-415, PF-416, PF-417, PF-418, PF-419, PF-421, PF-422, PF-423, PF-424, PF-425, PF-426, PF-427, PF-428, PF-429, PF-430, PF-431, PF-432, PF-433, PF-434, PF-437, PF-439, PF-440, PF-442, PF-443, PF-444, PF-445, PF-446, PF-447, PF-448, PF-449, PF-450, PF-451, PF-452, PF-453, PF-454, PF-455, PF-457, PF-458, PF-469, PF-460, PF-461, PF-462, PF-464, PF-465, PF-466, PF-467, PF-468, PF-469, PF-471, PF-472, PF-473, PF-474, PF-475, PF-476, PF-477, PF-478, PF-479, PF-480, PF-482, PF-485, PF-511, PF-512, PF-513, PF-514, PF-515, PF-516, PF-517, PF-518, PF-519, PF-520, PF-521, PF-522, PF-523, PF-524, PF-525, PF-526, PF-527, PF-528, PF-529, PF-530, PF-531, PF-532, PF-533, PF-534, PF-535, PF-536, PF-537, PF-538, PF-539, PF-540, PF-541, PF-542, PF-543, PF-544, PF-546, PF-548, PF-553, PF-555, PF-556, PF-558, PF-560, PF-562, PF-563, PF-566, PF-567, PF-572, PF-573, PF-575, PF-576, PF-577, PF-578, PF-580, PF-581, PF-583, PF-585, PF-585, PF-586, PF-587, PF-589, PF-591, PF-592, PF-595, PF-596, PF-598, PF-599, PF-600, PF-603, PF-605, PF-606, PF-607, PF-609, PF-610, PF-612, PF-614, PF-615, PF-617, PF-618, PF-619, PF-621, PF-622, PF-623, PF-624, PF-625, PF-626, PF-627, PF-629, PF-631, PF-632, PF-634, PF-635, PF-636, PF-637, PF-638, PF-639, PF-640, PF-643, PF-644, PF-645, PF-646, PF-647, PF-651, PF-652, PF-653, PF-654, PF-655, PF-657, PF-658, PF-659, PF-660, PF-662, PF-663, PF-664, PF-665, PF-666, PF-667, PF-668, PF-670, PF-672, PF-675, PF-677, PF-681, PF-682, PF-683, PF-684, PF-685, PF-686, PF-687, PF-688, PF-690, PF-691, PF-693, PF-694, PF-695, PF-696, PF-697, PF-698, PF-699, PF-700, PF-702, PF-704, PF-737, PF-741, PF-744, PF-745, PF-746, PF-748, PF-749, PF-752, PF-756, PF-757, PF-760, PF-761, PF-762, PF-763, PF-764, PF-770, PF-776, and PF-S003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of A. baumannii can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against A. baumannii in Tables 4, 5, or 6 (e.g., from the group consisting of PF-531, PF-006, PF-538, and PF-530).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of C. jejuni can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against C. jejuni in Tables 4, 5, or 6 (e.g., from the group consisting of PF-006, PF-008, PF-033, PF-040, PF-053, PF-056, PF-057, PF-059, PF-061, PF-063, PF-067, PF-068, PF-069, PF-071, PF-073, PF-140, PF-145, PF-148, PF-171, PF-175, PF-355, PF-356, PF-363, PF-366, PF-380, PF-389, PF-390, PF-392, PF-393, PF-411, PF-418, PF-422, PF-425, PF-426, PF-431, PF-432, PF-456, PF-469, PF-470, PF-471, PF-472, PF-473, PF-474, PF-475, PF-527, PF-548, PF-555, PF-556, PF-558, PF-559, PF-560, PF-562, PF-563, PF-564, PF-566, PF-567, PF-575, PF-576, PF-577, PF-581, PF-584, PF-585, PF-586, PF-590, PF-591, PF-592, PF-595, PF-596, PF-598, PF-599, PF-601, PF-605, PF-607, PF-609, PF-610, PF-614, PF-615, and PF-S003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of E. coli can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against E. coli in Tables 4, 5, or 6 (e.g., from the group consisting of PF-007, PF-040, PF-053, PF-057, PF-068, PF-178, PF-344, PF-347, PF-349, PF-350, PF-355, PF-360, PF-362, PF-363, PF-366, PF-369, PF-370, PF-374, PF-375, PF-376, PF-379, PF-380, PF-381, PF-383, PF-385, PF-386, PF-387, PF-390, PF-395, PF-396, PF-398, PF-399, PF-401, PF-403, PF-410, PF-411, PF-413, PF-418, PF-425, PF-426, PF-427, PF-432, PF-439, PF-440, PF-443, PF-444, PF-451, PF-452, PF-453, PF-454, PF-460, PF-469, PF-471, PF-473, PF-474, PF-478, PF-480, PF-514, PF-518, PF-519, PF-524, PF-526, PF-528, PF-530, PF-531, PF-532, PF-533, PF-534, PF-536, PF-540, PF-541, PF-543, PF-546, PF-576, PF-577, PF-578, PF-584, PF-586, PF-592, PF-595, PF-596, PF-598, PF-600, PF-603, PF-605, PF-606, PF-610, PF-612, PF-615, PF-619, PF-624, PF-634, PF-741, PF-746, PF-761, PF-770, and PF-776).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of F. nucleatum can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against F. nucleatum in Tables 4, 5, or 6 (e.g., from the group consisting of PF-0055, PF-0061, PF-0062, PF-0064, PF-0065, PF-0069, PF-0071, PF-0072, PF-0075, PF-C084, PF-0086, PF-0088, PF-0091, PF-0095, PF-0098, PF-C120, PF-C131, PF-C135, PF-C136, PF-C137, PF-C143, PF-C145, PF-C181, PF-C194, PF-C214, PF-C291, and PF-C293).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of M. Xanthus can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against M. Xanthus in Tables 4, 5, or 6 (e.g., from the group consisting of G-5, G-6, and G-7).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of P. aeruginosa can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against P. aeruginosa in Tables 4, 5, or 6 (e.g., from the group consisting of PF-053, PF-063, PF-067, PF-128, PF-140, PF-143, PF-168, PF-204, PF-209, PF-355, PF-356, PF-366, PF-380, PF-411, PF-425, PF-432, PF-454, PF-458, PF-471, PF-474, PF-527, PF-531, PF-535, PF-536, PF-575, PF-577, PF-605, PF-746, PF-761, and PF-S003).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of P. gingivalis can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against P. gingivalis in Tables 4, 5, or 6 (e.g., from the group consisting of PF-C052, PF-0072, PF-0075, PF-0084, PF-0088, PF-0089, PF-C136, PF-C180, PF-C194, and C293).
In certain embodiments a peptide or composition effective to kill or inhibit the growth and/or proliferation of P. mirabilis can comprise one or more peptides and/or one or more peptide domains comprising or consisting of sequences identified as having activity against P. mirabilis in Tables 4, 5, or 6 (e.g., from the group consisting of PF-040, PF-578, PF-612, PF-624, PF-634, PF-741, and PF-770).
It was also a surprising discovery that a number of novel antimicrobial peptides are characterized by the presence of particular amino acid motifs. Such motifs include KIF, FIK, KIH, HIK, and KIV, as illustrated in Table 7.
TABLE 7 Antimicrobial peptides characterized by particular motifs. Omnibus SEQ ID Motif # Sequence NO KIF PF-278 LSLATFA KIF MTRSNWSLKRFNRL 1567 PF-C059 QKIIDMSKFLFSLILFIMIVVIYIGKSIGGYSAIVSS 1568 IMLELDTVLYNK KIF FIYK PF-C073 FESLLPQATKKIVNNKGSKIN KIF 1569 PF-C085 KKF KIF VIINWFYHKYIILNFEENF 1570 PF-531 YIQFHLNQQPRPKVKKI KIF L 1571 PF-C194 NTNDLLQAFELMGLGMAGVFIVLGILYIVAELLI 1572 KIF PVNN PF-C201 IFKLFEEHLLYLLDAFYYS KIF RRLKQGLYRRKE 1573 QPYTQDLFRM PF-442 MQIFYIKT KIF LSFFLFLLIFSQCFYKIEE 1574 PF-C252 NYRLVNAIFS KIF KKKFIKF 1575 FIK PF-251 MAWK FIK LDKVVSQKECNNFLEKEENKKLLKL 1576 LRIQKNMR PF-261 MDIWK FIK SFNTVNTYLLLSCVLLIILVLYFYVI 1577 NPA PF-497 LVLRICTDLFT FIK WTIKQRKS 1578 PF-775 DLCGQE FIK FKTCVTNQLAKK 1579 PF-591 DLLKSLLGQDGAKNDEIIE FIK IIMEK 1580 PF-597 DEIKVSDEEIEK FIK ENNL 1581 PF-608 LICEVVKPEED FIK VKLNEDNVTAKISREFIAKKI 1582 DA IT-133 Y FIK DDNEALSKDWEVIGNDLKGTIDKYGKEFK 1583 VR PF-C252 NYRLVNAIFSKIFKKK FIK F 1584 PF-C278 DMKIIKLYIKILSFL FIK YCNKKLNSVKLKA 1585 PF-C290 GNVHPESDFHNLIQ FIK TFLYFTIFFKYFL 1586 PF-006 MGIIAGIIK FIK GLIEKFTGK 1587 PF-013 LIQKGLNQTFIVVIRLNN FIK KS 1588 PF-040 MIHLTKQNTMEALH FIK QFYDMFFILNFNV 1589 KIH PF-252 MKKLVAALAVIVILTGCVYDPVNYD KIH DQEF 1590 QDHLRQNG PF-575 LNFRAENKILE KIH ISLIDTVEGSA 1591 PF-533 KTPND KIH KTIIIKHIIL 1592 HIK PF-222 HIK ETR 1593 PF-319 SIGSMIGMYSFRHKTK HIK FTFGIPFILFLQFLLV 1594 YFYILK PF-477 HKNKLNIP HIK S 1595 KIV PF-272 MTLTIKIKHRS KIV PLNLISLVYAFFTYNFVANRI 1596 MFLTND PF-758 PEII KIV SGLL 1597 PF-336 MLTSRKKRLK KIV EEQNKKDESI 1598 PF-C073 FESLLPQATK KIV NNKGSKINKIF 1599 PF-721 TEQAK KIV DILNNWLE 1600 PF-730 FEDIEQIIKYHLIDG KIV APLLLDR 1601 PF-095 KRGS KIV IAIAVVLIVLAGVWVW 1602 PF-028 ALDCSEQSVILWYETILD KIV GVIK 1603 VIK PF-257 VWENRKKYLENEIERHNVFLKLGQE VIK GLNA 1604 LASRGR PF-226 LMFFSENMDKRDTLSGKFRYFAGSK VIK LMNW 1605 LSENGK PF-580 EILNNNQ VIK ELTMKYKTQFESNLGGWTARAR 1606 R PF-366 ALCS VIK AIELGIINVHLQ 1607 PF-C092 NGDKKAKEELDKWDE VIK ELNIQF 1608 PF-S028 GS VIK KRRKRMSKKKHRKMLRRTRVQRRKLG 1609 K PF-103 VIK ISVPGQVQMLIP 1610 PF-527 GS VIK KRRKRMAKKKHRKLLKKTRIQRRRAGK 1611 PF-167 AIEG VIK KGACFKLLRHEMF 1612 PF-C166 KRKHENVIVAEEMR VIK N 1613 PF-007 MGIIAGIIK VIK SLIEQFTGK 1614 PF-071 HCVIGNVVDIANLLKRRAVYRDIAD VIK MR 1615 PF-028 ALDCSEQSVILWYETILDKIVG VIK 1616 PRP PF-C031 WSESQPPTAT PRP HAEVARAGLVTPPTL 1617 PF-752 LHVIR PRP ELSELKFPITKILKVNKQGLKK 1618 PF-672 MRFGSLALVAYDSAIKHSW PRP SSVRRLRM 1619 PF-088 VMFVLTRGRS PRP MIPAY 1620 PF-143 LS PRP IIVSRRSRADNNNDWSR 1621 PF-168 VLPFPAIPLSRRRACVAA PRP RSRQRAS 1622 PF-531 YIQFHLNQQ PRP KVKKIKIFL 1623
All groups are associated with antimicrobial activity

In certain embodiments, peptides described herein can have multiple activities. Thus for example, a peptide can have both binding/targeting activity and antimicrobial activity. Illustrative peptides having multiple activities are shown in Table 8. Such peptides can be used, e.g., in a chimeric construct, for any or all of these properties. Thus, for example, a peptide designated “B” in Table 8 can be used as a targeting peptide. If it is also designated G or M it can also be used for antimicrobial activity.





TABLE 8



Peptides having multiple activities. B: targeting/binding activity;

M: antimicrobial activity; G: Growth or phenotype altering.






Peptide
Activities





PF-001
G B


PF-002
G B


PF-003
G B


PF-004
G B


PF-005
G B


PF-006
G B M


PF-007
G B


PF-008
G B


PF-009
G B


PF-010
G B


PF-011
G B


PF-012
G B


PF-013
G B


PF-015
G B


PF-017
G B


PF-020
G B


PF-021
G B


PF-022
G B


PF-023
G B


PF-024
G B


PF-025
G B


PF-026
G B


PF-027
G B


PF-028
G B


PF-029
G B


PF-030
G B


PF-031
G B


PF-033
G B


PF-034
G B


PF-035
G B


PF-036
G B


PF-037
G B


PF-040
G B


PF-041
G B


PF-042
G B


PF-043
G B


PF-045
G B


PF-046
G B


PF-048
G B


PF-049
G B


PF-051
G B


PF-052
G B


PF-053
G B


PF-056
G B


PF-057
G B


PF-058
G B


PF-061
G B


PF-063
G B


PF-064
G B


PF-065
G B


PF-066
G B


PF-067
G B


PF-068
G B


PF-069
G B


PF-070
G B


PF-071
G B


PF-073
G B


PF-074
G B


PF-075
G B


PF-076
G B


PF-099
G B


PF-123
G B


PF-124
G B


PF-125
G B


PF-127
G B


PF-128
G B


PF-129
G B


PF-133
G B


PF-135
G B


PF-137
G B


PF-139
G B


PF-140
G B


PF-143
G B


PF-144
G B


PF-145
G B


PF-148
G B M


PF-149
G B


PF-153
G B


PF-156
G B


PF-157
G B


PF-164
G B


PF-168
G B M


PF-171
G B


PF-173
G B


PF-175
G B


PF-176
G B


PF-178
G B


PF-180
G B


PF-186
G B


PF-188
G B


PF-190
G B


PF-191
G B


PF-192
G B


PF-196
G B


PF-203
G B


PF-204
G B


PF-208
G B


PF-209
G B M


PF-212
G B


PF-215
G B


PF-224
G B


PF-226
G B


PF-233
G B


PF-234
G B


PF-235
G B


PF-249
G B


PF-255
G B


PF-257
G B


PF-270
G B


PF-271
G B


PF-273
G B


PF-276
G B


PF-278
G B M


PF-283
G B M


PF-289
G B


PF-292
G B


PF-294
G B


PF-297
G B


PF-301
G B


PF-305
G B


PF-306
G B


PF-307
G B M


PF-313
G B


PF-319
G B


PF-322
G M


PF-344
G B


PF-347
G B


PF-349
G B


PF-350
G B


PF-354
G B


PF-355
G B


PF-356
G B


PF-357
G B


PF-360
G B


PF-362
G B


PF-363
G B


PF-366
G B


PF-369
G B


PF-370
G B


PF-373
G B


PF-374
G B


PF-375
G B


PF-376
G B


PF-378
G B


PF-379
G B


PF-380
G B


PF-381
G B


PF-382
G B


PF-383
G B


PF-385
G B


PF-386
G B


PF-387
G B


PF-389
G B


PF-390
G B


PF-392
G B


PF-393
G B


PF-394
G B


PF-395
G B


PF-396
G B


PF-397
G B


PF-398
G B


PF-399
G B


PF-401
G B


PF-403
G B


PF-404
G B


PF-405
G B


PF-406
G B


PF-407
G B


PF-408
G B


PF-410
G B


PF-411
G B


PF-413
G B


PF-414
G B


PF-416
G B


PF-417
G B


PF-418
G B


PF-421
G B


PF-422
G B


PF-423
G B


PF-424
G B


PF-425
G B


PF-426
G B


PF-427
G B


PF-428
G B


PF-429
G B


PF-430
G B


PF-431
G B


PF-432
G B


PF-433
G B


PF-434
G B


PF-437
G M


PF-439
G B


PF-440
G B


PF-442
G B


PF-443
G B


PF-444
G B


PF-445
G B


PF-446
G B


PF-447
G B


PF-S003
G B


PF-448
G B M


PF-450
G B


PF-451
G B


PF-452
G B


PF-453
G B


PF-454
G B


PF-456
G B


PF-457
G B


PF-458
G B


PF-459
G B


PF-460
G B


PF-461
G B


PF-462
G B


PF-464
G B


PF-465
G B


PF-466
G B


PF-467
G B


PF-469
G B


PF-470
G B


PF-471
G B


PF-472
G B


PF-473
G B


PF-474
G B


PF-475
G B


PF-476
G B


PF-477
G B


PF-478
G B


PF-479
G B


PF-480
G B


PF-482
G B


PF-484
G B


PF-497
B M


PF-499
B M


PF-511
G B M


PF-512
G B M


PF-513
G B


PF-514
G B


PF-515
G B


PF-516
G


PF-517
G B


PF-518
G B


PF-519
G B


PF-520
G B M


PF-521
G B M


PF-522
G B M


PF-523
B M


PF-524
G B M


PF-525
G M


PF-526
G B


PF-527
G B M


PF-528
G B


PF-529
G B M


PF-530
G M


PF-531
G M


PF-537
G B


PF-538
G M


PF-539
G B


PF-540
G B


PF-542
G B


PF-543
G B


PF-544
G B


PF-545
G B M


PF-546
G B


PF-547
G B M


PF-548
G B


PF-549
G B


PF-550
G B


PF-551
G B


PF-552
G B


PF-553
G B


PF-554
G B


PF-555
G B


PF-556
G B


PF-557
G B


PF-558
G B


PF-559
G B


PF-560
G B


PF-562
G B


PF-563
G B


PF-564
G B


PF-566
G B


PF-567
G B


PF-569
G B


PF-572
G B


PF-573
G B


PF-575
G B


PF-576
G B


PF-577
G B


PF-578
G B


PF-580
G B


PF-581
G B


PF-583
G B M


PF-584
G B


PF-585
G B


PF-586
G B


PF-587
G B


PF-588
G B


PF-589
G B


PF-590
G B


PF-592
G B


PF-593
G B


PF-594
G B


PF-595
G B


PF-596
G B


PF-597
G B


PF-598
G B


PF-599
G B


PF-600
G B M


PF-601
G B


PF-602
G B


PF-603
G B


PF-604
G B


PF-605
G B


PF-606
G M


PF-607
G B


PF-609
G B


PF-610
G B


PF-612
G B


PF-613
G B


PF-614
G B


PF-615
G B


PF-616
G B


PF-617
G B


PF-619
G B


PF-621
G B


PF-622
G B


PF-623
G B


PF-625
G B


PF-626
G B


PF-627
G B


PF-629
G B


PF-630
G B


PF-631
G B


PF-632
G B


PF-634
G B


PF-635
G B


PF-636
G B


PF-637
G B


PF-638
G B


PF-639
G B


PF-640
G B


PF-642
G B


PF-655
G B


PF-664
G B


PF-672
G B M


PF-681
G B


PF-686
G B


PF-737
G B


PF-738
G B


PF-741
G B


PF-744
G B


PF-745
G B


PF-746
G B


PF-748
G B


PF-749
G B


PF-752
G B


PF-756
G B


PF-757
G B


PF-760
G B


PF-761
G B


PF-762
G B


PF-763
G B


PF-764
G B


PF-770
G B


PF-776
G B


PF-C052
G B


PF-C055
G B


PF-C057
G B


PF-C058
G B


PF-C061
G B


PF-C062
G B


PF-C064
G B


PF-C065
G B


PF-C069
G B


PF-C071
G B


PF-C072
G B


PF-C075
G B


PF-C084
G B


PF-C085
G B


PF-C086
G B


PF-C088
G B


PF-C091
G B


PF-C095
G B


PF-C098
G B


PF-C120
G B


PF-C131
G B


PF-C135
G B


PF-C136
G B


PF-C137
G B


PF-C139
G B


PF-C142
G B


PF-C143
G B


PF-C145
G B


PF-C180
G B


PF-C181
G B


PF-C194
G B


PF-C281
G B


PF-C290
G B


PF-C291
G B





































































































































































































































































































































































































































Other peptides believed to show binding, growth altering, and/or antimicrobial activity are shown in Table 9.





TABLE 9



Additional peptides believed to have binding, growth

altering,mand/or antimicrobial activity.







SEQ

ID
Sequence
ID No.



PF-198
RRLASRRSLVVST
1624



PF-227
RLLGLYGENSAAGFIASVIGAVIILFIYNLIARKS
1625



PF-260
GHLRVCWILWLQSANPLSFRHHYLAVMW
1626



PF-261
MDIWKFIKSFNTVNTYLLLSCVLLIILVLYFYVINPA
1627



PF-277
MIIQNKKIEKIYKYQTKEIFLNKTSLRAGFVFRMVRVLI
1628



PF-280
MLIDWQEPDIEKSFCAAFLKISVSVLVYRTPLGYGNQLRE
1629



PF-286
FFDGEVGCGC
1630



PF-287
ILEQNIEEVFFIQS
1631



PF-312
MDKIRIWNNFHISNEYIKQRYGIISIPLFYVYLF
1632



PF-321
FAKKNPCRMRVPNTGTWYLVVNQDGNSGIVNFSINTIQN
1633



PF-327
MLVFQMRYQMRYVDKTSTVLKQTKNSDYADK
1634



PF-330
MLMNFEVYQQRILIIYNKCYHLKAVGKNLQLFIIVD
1635



PF-331
MGRHLWNPSYFVATVSENTEEQIRKYINNQKKQVK
1636



PF-341
DDKNEGKIAQGEY
1637



PF-391
EASVYRE
1638



PF-420
MVKHNFDVTDKTGKISSKHCFEITDKTDVV
1639



PF-708
DRPSQTTHHTLSSSRITGPS
1640



PF-710
EALLPPDPPDEDSQRIIPQ
1641



PF-713
DRPSQTTHHTLSSSRITGPS
1642



PF-715
LEDTKALFPCFVPI
1643



PF-718
KKYSSFKSMIDDLEYDA
1644



PF-719
FKSMIDDLEYDA
1645



PF-721
TEQAKKIVDILNNWLE
1646



PF-722
STSPSVTSVYAEALGLK
1647



PF-723
VGAMAIFLNVVAMLAGV
1648



PF-725
ARTIQNNGCLIHNSRYP
1649



PF-726
CDDLYALEAQGTLNELLKK
1650



PF-729
TPEPVVIVKP
1651



PF-730
FEDIEQIIKYHLIDGKIVAPLLLDR
1652



PF-734
SDIIAENIFQQGELEPMLRDAVAA
1653



PF-736
KGSASGSASGSGSAK
1654



PF-739
KSGASSVASAAKSG
1655



PF-742
AAATTATTAK
1656



PF-743
TKGTTTGTAKTTGVTTGTAK
1657



PF-769
GSRGGAKRGGARG
1658



PF-C031
WSESQPPTATPRPHAEVARAGLVTPPTL
1659



PF-C038
QPIGFPTDSVHGTDLVHRLRGTTSSR
1660



PF-C077
LENLDIEGLTEMKEHIEDLIAEKSAAESIEEVIVEAE
1661



PF-C205
AYSLTFQNPNDNLTDEEVAKYMEKITKALTEKIGAEVR
1662



PF-S016
PLTRETFAERGIRKARVARTFSEEEPPF
1663





































































































III. Design and Construction of STAMPs and Other Chimeric Constructs.
In various embodiments this invention provides chimeric moieties comprising one or more targeting moieties attached to one or more effectors. The targeting moieties can be selected to preferentially bind to a target microorganism (e.g., bacteria, virus, fungi, yeast, alga, protozoan, etc.) or group of microorganisms (e.g., gram-negative or gram-positive bacteria, particular genus, species, etc.) In certain embodiments the targeting moiety comprises one or more novel microorganism-binding peptides as described herein (see, e.g., Table 3, and/or Table 10, and/or Table 12). In certain embodiments the targeting moiety comprises non-peptide moieties (e.g., antibodies, receptor, receptor ligand, lectin, and the like).
In various embodiments the effector comprises a moiety whose activity is to be delivered to the target microorganism(s), to a biofilm comprising the target microorganism(s), to a cell or tissue comprising the target microorganism(s), and the like. In certain embodiments the targeting moiety comprises one or more antimicrobial peptide(s) as described herein (see, e.g., Tables 4, 5 and/or 14), an antibiotic (including, but not limited to a steroid antibiotic), a detectable label, a porphyrin, a photosensitizing agent, an epitope tag, a lipid or liposome, a nanoparticle, a dendrimer, and the like.
In certain embodiments one or more targeting moieties are attached to a single effector. In certain embodiments one or more effectors are attached to a single targeting moiety. In certain embodiments multiple targeting moieties are attached to multiple effectors. The targeting moieties(s) can be attached directly to the effector(s) or through a linker. Where the targeting moiety and the effector comprise peptides the chimeric moiety can be a fusion protein.
A) Targeting Moieties.
In various embodiments this invention provides targeting moieties that preferentially and/or specifically bind to a microorganism (e.g., a bacterium, a fungus, a yeast, etc.). One or more such targeting moieties can be attached to one or more effectors to provide chimeric moieties that are capable of delivering the effector(s) to a target (e.g., a bacterium, a fungus, a yeast, a biofilm comprising the bacterium or fungus or yeast, etc.).
In various embodiments, targeting moieties include, but are not limited to peptides that preferentially bind particular microorganisms (e.g., bacteria, fungi, yeasts, protozoa, algae, viruses, etc.) or groups of such microorganisms, e.g., as described above, antibodies that bind particular microorganisms or groups of microorganisms, receptor ligands that bind particular microorganisms or groups of microorganisms, porphyrins (e.g., metalloporphyrins), lectins that bind particular microorganisms or groups of microorganisms, and the like. As indicated it will be appreciated that references to microorganisms or groups of microorganism include bacteria or groups of bacteria, viruses or groups of viruses, yeasts or groups of yeasts, protozoa or groups of protozoa, viruses or groups of viruses, and the like.
i. Targeting Peptides.
In certain embodiments, the targeting moiety comprises one or more targeting peptides that bind particular bacteria, fungi, and/or yeasts, and/or algae, and/or viruses and/or that bind particular groups of bacteria, and/or groups of fungi, and/or groups of yeasts, and/or groups of algae.
In certain embodiments the targeting peptide can comprise one or more domains capable of binding, specifically binding, or preferentially binding to a microorganism, e.g., a target microbial organism (see, e.g., Table 3). In certain embodiment, the targeting peptide be identified via screening peptide libraries. For example, a phage display peptide library can be screened against a target microbial organism or a desired antigen or epitope thereof. Any peptide identified through such screening can be used as a targeting peptide for the target microbial organism. Illustrative additional targeting peptides are shown in Table 10.
TABLE 10 Additional illustrative targeting moieties. Targeting Moiety/ SEQ ID Organism Structure/sequence NO LPSB-1 RGLRRLGRRGLRRLGR 1664 Phob-1 KPVLPVLPVLPVL 1665 LPSB-2 VLRIIRIAVLRIIRIA 1666 LPTG-1 LPETGGSGGSLPETG 1667 α-1 RAHIRRAHIRR 1668 ANION-1 DEDEDDEEDDDEEE 1669 PHILIC-1 STMCGSTMCGSTMCG 1670 SA5.1/ S. aureus VRLPLWLPSLNE 1671 SA5.3/ S. aureus ANYFLPPVLSSS 1672 SA5.4/ S. aureus SHPWNAQRELSV 1673 SA5.5/ S. aureus SVSVGMRPMPRP 1674 SA5.6/ S. aureus WTPLHPSTNRPP 1675 SA5.7/ S. aureus SVSVGMKPSPRP 1676 SA5.8/ S. aureus SVSVGMKPSPRP 1677 SA5.9/ S. aureus SVPVGPYNESQP 1678 SA5.10/ S. aureus WAPPLFRSSLFY 1679 SA2.2/ S. aureus WAPPXPXSSLFY 1680 SA2.4/ S. aureus HHGWTHHWPPPP 1681 SA2.5/ S. aureus SYYSLPPIFHIP 1682 SA2.6/ S. aureus HFQENPLSRGGEL 1683 SA2.7/ S. aureus FSYSPTRAPLNM 1684 SA2.8/ S. aureus SXPXXMKXSXXX 1685 SA2.9/ S. aureus VSRHQSWHPHDL 1686 SA2.10/ S. aureus DYXYRGLPRXET 1687 SA2.11/ S. aureus SVSVGMKPSPRP 1688 S. aureus/ V/Q/H-P/H-H-E-F/Y-K/H-H/A-L/H-X-X-K/R-P/L 1689 Consensus DH5.1/ E coli . KHLQNRSTGYET 1690 DH5.2/ E coli . HIHSLSPSKTWP 1691 DH5.3/ E coli . TITPTDAEMPFL 1692 DH5.4/ E coli . HLLESGVLERGM 1693 DH5.5/ E coli . HDRYHIPPLQLH 1694 DH5.6/ E coli . VNTLQNVRHMAA 1695 DH5.7/ E coli . SNYMKLRAVSPF 1696 DH5.8/ E coli . NLQMPYAWRTEF 1697 DH5.9/ E coli . QKPLTGPHFSLI 1698 CSP/ S. mutans SGSLSTFFRLFNRSFTQALGK 1699 CSPC18/ S. mutans LSTFFRLFNRSFTQALGK 1700 CSPC16/ S. mutans TFFRLFNRSFTQALGK 1701 CSPM8/ S. mutans TFFRLFNR 1702 KH/ Pseudomonas spp KKHRKHRKHRKH 1703 (US 2004/0137482) cCF10 LVTLVFV 1704 AgrD1 YSTCDFIM 1705 AgrD2 GVNACSSLF 1706 AgrD3 YINCDFLL 1707 NisinA ITSISLCTPGCKTGALMGCNMRTATCIICSIIIVSK 1708 PlnA KSSAYSLQMGATAIKQVKKLFKKWGW 1709 S3L1-5 WWYNWWQDW 1710 Penetratin RQIKIWFWNRRMKWKK* 1711 Tat EHWSYCDLRPG 1712 Pep-1N KETWWETWWTEW 1713 Pep27 MRKEFHNVLS SGQLLADKRPARDYNRK 1714 HABP35 LKQKIKHVVKLKVVVKLRSQLVKRKQN 1715 HABP42 (all D) STMMSRSHKTRSHHV 1716 HABP52 GAHWQFNALTVRGGGS 1717 Hi3/17 KQRTSIRATEGCLPS 1718 α- E.coli peptide QEKIRVRLSA 1719 Salivary Receptor QLKTADLPAGRDETTSFVLV* 1720 Adhesion Fragment S1 (Sushi frag.) GFKLKGMARISCLPNGQWSNFPPKCIRECAMVSS 1721 (LPS binding) S3 (Sushi frag.) HAEHKVKIGVEQKYGQFPQGTEVTYTC SGNYFL 1722 (LPS binding) M MArg.1 AMDMYSIEDRYFGGYAPEVG 1723 (Mycoplasma infected cell line binding peptide BPI fragment 1 ASQQGTAALQKELKRIKPDYSDSFKIKH 1724 (LPS binding) 6,376,462 BPI fragment 2 SSQISMVPNVGLKFSISNANIKISGKWKAQKRFL 1725 (LPS binding) K 6,376,462 BPI fragment 3 VHVHISKSKVGWLIQLFHKKIESALRNK 1726 (LPS binding) 6,376,462 LBP fragment 1 AAQEGLLALQSELLRITLPDFTGDLRIPH 1727 (LPS binding) 6,376,462 LBP fragment 2 HSALRPVPGQGLSLSISDSSIRVQGRWKVRKSFF 1728 (LPS binding) K 6,376,462 LBP fragment 3 VEVDMSGDLGWLLNLFHNQIESKFQKV 1729 (LPS binding) 6,376,462 B. anthracis spore ATYPLPIR 1730 binding (WO/1999/036081) Bacillus peptides of 5-12 amino acids containing the 1731 sporebinding sequence (WO/1999/036081) Asn-His-Phe-Leu peptides of 5-12 amino acids containing the 1732 sequence Asn-His-Phe-Leu-Pro Thr-Ser-Glu-Asn-Val-Arg-Thr (TSQNVRT) 1733 A peptide of formula Thr-Tyr-Pro-X-Pro-X-Arg 1734 (TYPXPXR) where X is a Ile, Val or Leu. A peptide having the sequence TSQNVRT. 1735 A peptide having the sequence TYPLPIR 1736 LPS binding peptide TFRRLKWK 1737 1 (6,384,188) LPS BP 2 (6,384,188) RWKVRKSFFKLQ 1738 LPS BP 3 (6,384,188) KWKAQKRFLKMS 1739 Pseudomonas pilin KCTSDQDEQFIPKGCSK 1740 binding peptide (5,494,672) RNAII inhibiting YSPWTNF 1741 peptide (S. Aureus)
Patents and patent publications disclosing the referenced antibodies are identified in the table.

In certain embodiments the targeting moieties can comprise other entities, particularly when utilized with an antimicrobial peptide as described, for example, in Table 4. Illustrative targeting moieties can include a polypeptide, a peptide, a small molecule, a ligand, a receptor, an antibody, a protein, or portions thereof that specifically interact with a target microbial organism, e.g., the cell surface appendages such as flagella and pili, and surface exposed proteins, lipids and polysaccharides of a target microbial organism.
ii. Targeting Antibodies.
In certain embodiments the targeting moieties can comprise one or more antibodies that bind specifically or preferentially a microorganism or group of microorganisms (e.g., bacteria, fungi, yeasts, protozoa, viruses, algae, etc.). The antibodies are selected to bind an epitope characteristic or the particular target microorganism(s). In various embodiments such epitopes or antigens are typically is gram-positive or gram-negative specific, or genus-specific, or species-specific, or strain specific and located on the surface of a target microbial organism. The antibody that binds the epitope or antigen can direct an anti-microbial peptide moiety or other effector to the site. Furthermore, in certain embodiments the antibody itself can provide anti-microbial activity in addition to the activity provided by effector moiety since the antibody may engage an immune system effector (e.g., a T-cell) and thereby elicit an antibody-associated immune response, e.g., a humoral immune response.
Antibodies that bind particular target microorganisms can be made using any methods readily available to one skilled in the art. For example, as described in U.S. Pat. No. 6,231,857 (incorporated herein by reference) three monoclonal antibodies, i.e., SWLA1, SWLA2, and SWLA3 have been made against S. mutans . Monoclonal antibodies obtained from non-human animals to be used in a targeting moiety can also be humanized by any means available in the art to decrease their immunogenicity and increase their ability to elicit anti-microbial immune response of a human. Illustrative microorganisms and/or targets to which antibodies may be directed are shown, for example, in Tables 3 and 11.
Various forms of antibody include, without limitation, whole antibodies, antibody fragments (e.g., (Fab′) 2 Fab′, etc.), single chain antibodies (e.g., scFv), minibodies, Di-miniantibody, Tetra-miniantibody, (scFv) 2 , Diabody, scDiabody, Triabody, Tetrabody, Tandem diabody, VHH, nanobodies, affibodies, unibodies, and the like.
Methods of making such antibodies are well known to those of skill in the art. In various embodiments, such methods typically involve providing the microorganism, or a component thereof for use as an antigen to raise an immune response in an organism or for use in a screening protocol (e.g., phage or yeast display).
For example, polyclonal antibodies are typically raised by one or more injections (e.g. subcutaneous or intramuscular injections) of the target microorganism(s) or components thereof into a suitable non-human mammal (e.g., mouse, rabbit, rat, etc.).
If desired, the immunizing microorganism or antigen derived therefrom can be administered with or coupled to a carrier protein by conjugation using techniques that are well-known in the art. Such commonly used carriers which are chemically coupled to the peptide include keyhole limpet hemocyanin (KLH), thyroglobulin, bovine serum albumin (BSA), and tetanus toxoid. The coupled peptide is then used to immunize the animal (e.g. a mouse or a rabbit).
The antibodies are then obtained from blood samples taken from the mammal. The techniques used to develop polyclonal antibodies are known in the art (see, e.g., Methods of Enzymology , “Production of Antisera With Small Doses of Immunogen: Multiple Intradermal Injections”, Langone, et al. eds. (Acad. Press, 1981)). Polyclonal antibodies produced by the animals can be further purified, for example, by binding to and elution from a matrix to which the peptide to which the antibodies were raised is bound. Those of skill in the art will know of various techniques common in the immunology arts for purification and/or concentration of polyclonal antibodies, as well as monoclonal antibodies see, for example, Coligan, et al. (1991) Unit 9 , Current Protocols in Immunology , Wiley Interscience).
In certain embodiments the antibodies produced will be monoclonal antibodies (“mAb's”). The general method used for production of hybridomas secreting mAbs is well known (Kohler and Milstein (1975) Nature, 256:495
Antibody fragments, e.g. single chain antibodies (scFv or others), can also be produced/selected using phage display and/or yeast display technology. The ability to express antibody fragments on the surface of viruses that infect bacteria (bacteriophage or phage) or yeasts makes it possible to isolate a single binding antibody fragment, e.g., from a library of greater than 10 10 nonbinding clones. To express antibody fragments on the surface of phage (phage display) or yeast, an antibody fragment gene is inserted into the gene encoding a phage surface protein (e.g., pIII) and the antibody fragment-pIII fusion protein is displayed on the phage surface (McCafferty et al. (1990) Nature, 348: 552-554; Hoogenboom et al. (1991) Nucleic Acids Res. 19: 4133-4137).
Since the antibody fragments on the surface of the phage or yeast are functional, phage bearing antigen binding antibody fragments can be separated from non-binding phage by antigen affinity chromatography (McCafferty et al. (1990) Nature, 348: 552-554). Depending on the affinity of the antibody fragment, enrichment factors of 20 fold-1,000,000 fold are obtained for a single round of affinity selection.
Human antibodies can be produced without prior immunization by displaying very large and diverse V-gene repertoires on phage (Marks et al. (1991) J. Mol. Biol. 222: 581-597.
In certain embodiments, nanobodies can be used as targeting moieties. Methods of making V h H (nanobodies) are also well known to those of skill in the art. The Camelidae heavy chain antibodies are found as homodimers of a single heavy chain, dimerized via their constant regions. The variable domains of these camelidae heavy chain antibodies are referred to as V HH domains or V HH , and can be either used per se as nanobodies and/or as a starting point for obtaining nanobodies. Isolated V HH retain the ability to bind antigen with high specificity (see, e.g., Hamers-Casterman et al. (1993) Nature 363: 446-448). In certain embodiments such V HH domains, or nucleotide sequences encoding them, can be derived from antibodies raised in Camelidae species, for example in camel, dromedary, llama, alpaca and guanaco. Other species besides Camelidae (e.g. shark, pufferfish) can produce functional antigen-binding heavy chain antibodies, from which (nucleotide sequences encoding) such naturally occurring V HH can be obtained, e.g. using the methods described in U.S. Patent Publication US 2006/0211088.
In various embodiments, for use in therapy, human proteins are preferred, primarily because they are not as likely to provoke an immune response when administered to a patient. Comparisons of camelid V HH with the V H domains of human antibodies reveals several key differences in the framework regions of the camelid V HH domain corresponding to the V H /V L interface of the human V H domains. Mutation of these human residues to V HH resembling residues has been performed to produce “camelized” human V H domains that retain antigen binding activity, yet have improved expression and solubility.
Libraries of single V H domains have also been derived for example from V H genes amplified from genomic DNA or from mRNA from the spleens of immunized mice and expressed in E. coli (Ward et al. (1989) Nature 341: 544-546) and similar approaches can be performed using the V H domains and/or the V L domains described herein. The isolated single VH domains are called “dAbs” or domain antibodies. A “dAb” is an antibody single variable domain (V H or V L ) polypeptide that specifically binds antigen. A “dAb” binds antigen independently of other V domains; however, as the term is used herein, a “dAb” can be present in a homo- or heteromultimer with other V H or V L domains where the other domains are not required for antigen binding by the dAb, i.e., where the dAb binds antigen independently of the additional V H or V L domains.
As described in U.S. Patent Publication US 2006/0211088 methods are known for the cloning and direct screening of immunoglobulin sequences (including but not limited to multivalent polypeptides comprising: two or more variable domains—or antigen binding domains—and in particular V H domains or V HH domains; fragments of V L , V H or V HH domains, such as CDR regions, for example CDR3 regions; antigen-binding fragments of conventional 4-chain antibodies such as Fab fragments and scFv's, heavy chain antibodies and domain antibodies; and in particular of V H sequences, and more in particular of V HH sequences) that can be used as part of and/or to construct such nanobodies.
Methods and procedures for the production of VHH/nanobodies can also be found for example in WO 94/04678, WO 96/34103, WO 97/49805, WO 97/49805 WO 94/25591, WO 00/43507 WO 01/90190, WO 03/025020, WO 04/062551, WO 04/041863, WO 04/041865, WO 04/041862, WO 04/041867, PCT/BE2004/000159, Hamers-Casterman et al. (1993) Nature 363: 446; Riechmann and Muyldermans (1999) J. Immunological Meth., 231: 25-38; Vu et al. (1997) Molecular Immunology, 34(16-17): 1121-1131; Nguyen et al. (2000) EMBO J., 19(5): 921-930; Arbabi Ghahroudi et al. (19997) FEBS Letters 414: 521-526; van der Linden et al. (2000) J. Immunological Meth., 240: 185-195; Muyldermans (2001) Rev. Molecular Biotechnology 74: 277-302; Nguyen et al. (2001) Adv. Immunol. 79: 261, and the like.
In certain embodiments the antibody targeting moiety is a unibody. Unibodies provide an antibody technology that produces a stable, smaller antibody format with an anticipated longer therapeutic window than certain small antibody formats. In certain embodiments unibodies are produced from IgG4 antibodies by eliminating the hinge region of the antibody. Unlike the full size IgG4 antibody, the half molecule fragment is very stable and is termed a uniBody. Halving the IgG4 molecule left only one area on the UniBody that can bind to a target. Methods of producing unibodies are described in detail in PCT Publication WO2007/059782, which is incorporated herein by reference in its entirety (see, also, Kolfschoten et al. (2007) Science 317: 1554-1557).
Affibody molecules are class of affinity proteins based on a 58-amino acid residue protein domain, derived from one of the IgG-binding domains of staphylococcal protein A. This three helix bundle domain has been used as a scaffold for the construction of combinatorial phagemid libraries, from which Affibody variants that target the desired molecules can be selected using phage display technology (see, e.g., Nord et al. (1997) Nat. Biotechnol. 15: 772-777; Ronmark et al. (2002) Eur. J Biochem., 269: 2647-2655.). Details of Affibodies and methods of production are known to those of skill (see, e.g., U.S. Pat. No. 5,831,012 which is incorporated herein by reference in its entirety).
It will also be recognized that antibodies can be prepared by any of a number of commercial services (e.g., Berkeley antibody laboratories, Bethyl Laboratories, Anawa, Eurogenetec, etc.).
Illustrative antibodies that bind various microorganisms are shown in Table 11.





TABLE 11



Illustrative antibodies that bind target microorganisms.




Source
Antibody



U.S. Pat. No. 7,195,763
Polyclonal/monoclonal binds specific


Gram(+) cell wall repeats

U.S. Pat. No. 6,939,543
Antibodies against G(+) LTA

U.S. Pat. No. 7,169,903
Antibodies against G(+) peptidoglycan

U.S. Pat. No. 6,231,857
Antibody against S. mutans (Shi)

U.S. Pat. No. 5,484,591
Gram(−) binding antibodies

US 2007/0231321
Diabody binding to Streptococcus surface


antigen I/II

US 2003/0124635
Antibody against S. mutans

US 2006/0127372
Antibodies to Actinomyces naeslundii ,



Lactobacillus casei


US 2003/0092086
Antibody to S. sobrinus

U.S. Pat. No. 7,364,738
Monoclonal antibodies to the ClfA protein


in S. aureus

U.S. Pat. No. 7,632,502
Antibodies against C. albicans

U.S. Pat. No. 7,608,265
Monoclonal against C. difficile

U.S. Pat. No. 4,777,136
Monoclonal Antibodies against



Pseudomonas aeruginosa


see, e.g., ab20429, ab20560,
Antibody against S. pneumoniae

ab79522, ab35165, ab65602

from AbCAMm Cambridge

Science Park, U.K.










































In addition, antibodies (targeting moieties) that bind other microorganisms can readily be produced using, for example, the methods described above.
iii. Porphyrins.
In certain embodiments porphyrins, or other photosensitizing agents, can be used as targeting moieties in the constructs described herein. In particular, metalloporphyrins, particularly a number of non-iron metalloporphyrins mimic heme in their molecular structure and are actively accumulated by bacteria via high affinity heme-uptake systems. The same uptake systems can be used to deliver antibiotic-porphyrin and antibacterial-porphyrin conjugates. Illustrative targeting porphyrins suitable for this purpose are described in U.S. Pat. No. 6,066,628 and shown herein, for example, in FIGS. 1 and 2 .
For example, certain artificial (non-iron) metalloporphyrins (MPs) (Ga-IX, Mn-IX,) are active against Gram-negative and Gram-positive bacteria and acid-fast bacilli (e.g., Y. enterocolitica, N. meningitides, S. marcescens, E. coli, P. mirabilis, K pneumoniae, K. oxytoca, Ps. aeruginosa, C. freundii, E. aerogenes, F. menigosepticum, S. aureus, B. subtilis, S. pyogenes A, E. faecalis, M. smegmatis, M. bovis, M. tuber., S. crevisiae ) as described in Tables 1-5 of U.S. Pat. No. 6,066,628. These MPs can be used as targeting moieties against these microorganisms.
Similarly, some MPs are also growth-inhibitory against yeasts, indicating their usefulness targeting moieties to target Candida species (e.g., Candida albicans, C. krusei, C. pillosus, C. glabrata , etc.) and other mycoses including but not limited to those caused by as Trichophyton, Epidermophyton, Histoplasma, Aspergillus, Cryptococcus , and the like.
Porphyrins, and other photosensitizers, also have antimicrobial activity. Accordingly, in certain embodiments, the porphyrins, or other photosensitizers, can be used as effectors (e.g., attached to targeting peptides as described herein). In various embodiments the porphyrins or other photosensitizers can provide a dual functionality, e.g., as a targeting moiety and an antimicrobial and can be attached to a targeting peptide and/or to an antimicrobial peptide as described herein.
Illustrative porphyrins and other photosensitizers are shown in FIGS. 1-11 and described in more detail in the discussion of effectors below.
iv. Pheromones.
In certain embodiments, pheromones from microorganisms can be used as targeting moieties. Illustrative pheromones from bacteria and fungi are shown in Table 12.





TABLE 12



Illustrative bacterial and fungal pheromones utilizable as targeting moieties.






Locus tag
Product
Sequence
SEQ ID



Bacterial Pheromones




gi|1041118|dbj|BAA11198.1|
iPD1 [ Enterococcus faecalis ]
MKQQKKHIAALLF
1742



ALILTLVS




gi|l113947|gb|AAB35253.1|
iAM373sex pheromone
SIFTLVA
1743


inhibito [ Enterococcus




faecalis , Peptide, 7 aa]





gi|115412|sp|1313268.1|CAD1_
Sex pheromone CAD1
LFSLVLAG
1744

ENTFA






gi|116406|sp|P11932.1|CIA_
Sex pheromone cAM373
AIFILAS
1745

ENTFA
(Clumping-inducing




agent) (CIA)





gi|117240|sp|P13269.1|CPD1_
Sex pheromone cPD1
FLVMFLSG
1746

ENTFA






gi|12056953|gb|AAG48144.1|
putative peptide
DSIRDVSPTFNKIRR
1747

AF322594_1
pheromone PrcA
WFDGLFK



[ Lactobacillus paracasei ]





gi|123988|sp|P24803.1|IAD1_
Sex pheromone inhibitor
MSKRAMKKIIPLIT
1748

ENTFA
determinant precursor
LFVVTLVG



(iAD1)





gi|126362994|emb|CAM35812 .1|
precursor of pheromone
KDEIYWKPS
1749


peptide ComX [ Bacillus




amyloliquefaciens FZB42]





gi|1587088|prf|2205353A
pheromone
YSTCDFIM
1750



gi|15900442|ref|NP_345046.1|
peptide pheromone BlpC
GLWEDLLYNINRY
1751


[ Streptococcus
AHYIT



pneumoniae TIGR4]





gi|1617436|emb|CAA66791.1|
competence pheromone
DIRHRINNSIWRDIF
1752


[ Streptococcus gordonii ]
LKRK




gi|1617440|emb|CAA66786.1|
competence pheromone
DVRSNKIRLWWEN
1753


[ Streptococcus gordonii ]
IFFNKK




gi|18307870|gb|AAL67728.1|
ComX pheromone
PTTREWDG
1754

AF456134_2
precursor [ Bacillus




mojavensis ]





gi|18307874|gb|AAL67731.1|_
ComX pheromone
LQIYTNGNWVPS
1755

AF456135_2
precursor [ Bacillus




mojavensis ]





gi|29377808|ref|NP_816936.1|
sex pheromone inhibitor
MSKRAMKKIIPLIT
1756


determinant [ Enterococcus
LFVVTLVG



faecalis V583]





gi|3342125|gb|AAC27522.1|
putative pheromone
GAGKNLIYGMGYG
1757


[ Enterococcus faecium ]
YLRSCNRL




gi|41018893|sp|P60242.1|CSP1_
Competence-stimulating
EMRLSKFFRDFILQ
1758

STRPN
peptide type 1 precursor
RKK



(CSP-1)





gi|57489126|gb|AAW51333.1|
PcfP [ Enterococcus
WSEIEINTKQSN
1759


faecalis ]





gi|57489152|gb|AAW51349.1|
PrgT [ Enterococcus
HISKERFEAY
1760


faecalis ]





gi|58616083|ref|YP_195761.1|
UvaF [ Enterococcus
KYKCSWCKRVYTL
1761


faecalis ]
RKDHRTAR




gi|58616111|ref|YP_195802.1|
PcfP [ Enterococcus
WSEIEINTKQSN
1762


faecalis ]





gi|58616132|ref|YP_195769.1|
PrgQ [ Enterococcus
MKTTLKKLSRYIA
1763


faecalis ]
VVIAITLIFI




gi|58616137|ref|YP_195772.1|
PrgT [ Enterococcus
HISKERFEAY
1764


faecalis ]





gi|6919848|sp|O33689.1|CSP_
Competence-stimulating
DKRLPYFFKHLFSN
1765

STROR
peptide precursor (CSP)
RTK




gi|6919849|sp|O33666.1|CSP2_
Competence-stimulating
EMRKPDGALFNLF
1766

STRMT
peptide precursor (CSP)
RRR




gi|6919850|sp|O33668.1|CSP3_
Competence-stimulating
EMRKSNNNFFHFL
1767

STRMT
peptide precursor (CSP)
RRI




gi|6919851|sp|O33672.1|CSP1_
Competence-stimulating
ESRLPKIRFDFIFPR
1768

STRMT
peptide precursor (CSP)
KK




gi|6919852|sp|O33675.1|CSP4_
Competence-stimulating
EIRQTHNIFFNFFKR
1769

STRMT
peptide precursor (CSP)
R




gi|6919853|sp|O33690.1|CSP2_
Competence-stimulating
DWRISETIRNLIFPR
1770

STROR
peptide precursor (CSP)
RK




gi|999344|gb|AAB34501.1|
cOB1 bacterial sex
VAVLVLGA
1771


pheromone [ Enterococcus




faecalis , Peptide, 8 aa]





gi|18307878|gb|AAL67734.1|
ComX pheromone
FFEDDKRKSFI
1772

AF456136_2
precursor [ Bacillus




subtilis ]





gi|18307882|gb|AAL67737.1|
ComX pheromone
FFEDDKRKSFI
1773

AF456137_2
precursor [ Bacillus




subtilis ]





gi|28272731|emb|CAD65660.1|
accessory gene regulator
MKQKMYEAIAHLF
1774


protein D, peptide
KYVGAKQLVMCC



pheromone precursor
VGIWFETKIPDELR



[ Lactobacillus plantarum
K



WCFS1]





gi|28379890|ref|NP_786782.1|
accessory gene regulator
MKQKMYEAIAHLF
1775


protein D, peptide
KYVGAKQLVMCC



pheromone precursor
VGIWFETKIPDELR



[ Lactobacillus plantarum
K



WCFS1]





gi|57489105|gb|AAW51312.1|
PrgF [ Enterococcus
VVAYVITQVGAIRF
1776


faecalis ]





gi|58616090|ref|YP_195779.1|
PrgF [ Enterococcus
VVAYVITQVGAIRF
1777


faecalis ]





gi|58616138|ref|YP_195762.1|
PrgN [ Enterococcus
LLKLQDDYLLHLE
1778


faecalis ]
RHRRTKKIIDEN




gi|57489117|gb|AAW51324.1|
Pcff [ Enterococcus
EDIKDLTDKVQSLN
1779


faecalis ]
ALVQSELNKLIKRK




DQS




gi|57489119|gb|AAW51326.1|
PcfH [ Enterococcus
WFLDFSDWLSKVP
1780


faecalis ]
SKLWAE




gi|58616102|ref|YP_195792.1|
Pcff [ Enterococcus
EDIKDLTDKVQSLN
1781


faecalis ]
ALVQSELNKLIKRK




DQS




gi1586161041ref1YP_195794.11
PcfH [ Enterococcus
WFLDFSDWLSKVP
1782


faecalis ]
SKLWAE






Fungi






gi|1127585|gb|AAA99765.1|
mfa1 gene product
MLSIFAQTTQTSAS
1783



EPQQSPTAPQGRDN




GSPIGYSSCVVA




gi|1127592|gbIAAA99771.1|
mfa2 gene product
MLSIFETVAAAAPV
1784



TVAETQQASNNEN




RGQPGYYCLIA




gi|11907715|gb|AAG41298.1|
pheromone precursor
PSLPSSPPSLLPPLPL
1785


MFalpha1D
LKLLATRRPTLVG



[ Cryptococcus neoformans
MTLCV



var. neoformans ]





gi|13810235|emb|CAC37424.1|
M-factor precursor Mfm1
MDSMANSVSSSSV
1786


[ Schizosaccharomyces
VNAGNKPAETLNK



pombe ]
TVKNYTPKVPYMC




VIA




gi|14269436|gb|AAK58071.1|
peptide mating pheromone
MDTFTYVDLAAVA
1787

AF378295_1
precursor Bbp2-3
AAAVADEVPRDFE



[ Schizophyllum
DQITDYQSYCIIC



commune ]





gi|14269440|gb|AAK58073.1|
peptide mating pheromone
SNVHGWCVVA
1788

AF378297_1
precursor Bbp2-1




[ Schizophyllum




commune ]





gi|1813600|gb|AAB41859.1|
pheromone precursor
NTTAHGWCVVA
1789


Bbp1(1) [ Schizophyllum




commune ]





gi|24940428|emb|CAD56313.1|
a-pheromone
MQPSTVTAAPKDK
1790


[ Saccharomyces
TSAEKKDNYIIKGV



paradoxus ]
FWDPAC VIA




gi|27549492|gb|AA017258.1|
pheromone phb3.1
GPTWWCVNA
1791


[ Coprinopsis cinerea ]





gi|27549494|gb|AA017259.1|
pheromone phb3.2
SGPTWFCIIQ
1792


[ Coprinopsis cinerea ]





gi|27752314|gb|AA019469.1|
pheromone protein a
FTAIFSTLSSSVASK
1793


pecursor [ Cryptococcus
TDAPRNEEAYSSG



neoformans var. grubii ] NSP





gi|2865510|gb|AACO2682.1|
MAT-1 pheromone
MFSIFAQPAQTSVS
1794


[ Ustilago hordei ]
ETQESPANHGANP




GKSGSGLGYSTCV




VA




gi|3023372|sp|P78742.1|BB11_
RecName: Full = Mating-
NTTAHGWCVVA
1795

SCHCO
type pheromone BBP1(1);




Flags: Precursor





gi|3025079|sp|P56508.1|SNA2
RecName: Full = Protein
SDDNYGSLA
1796


YEAST SNA2





gi|37626077|gb|AAQ96360.1|
pheromone precursor Phb3
NGLTFWCVIA
1797


B5 [ Coprinopsis cinerea ]





gi|37626081|gb|AAQ96362.1|
pheromone precursor
PSWFCVIA
1798


Phb3.2 B45 [ Coprinopsis




cinerea ]





gi|37626083|gb|AAQ96363.1|
pheromone precursor
ASWFCTIA
1799


Phb3.1 B47 [ Coprinopsis




cinerea ]





gi|37961432|gb|AAP57503.1|
5te3-like pheromone
PHHKIANASDKRR
1800


receptor [ Thanatephorus
RMYFEIFMCAVL



cucumeris]





gi|400250|sp|P31962.1|MFA1_
RecName: Full = A1-
MLSIFAQTTQTSAS
1801

USTMA
specific pheromone;
EPQQSPTAPQGRDN



AltName: Full = Mating
GSPIGYSSCVVA



factor A1





gi|400251|sp|P31963.1|MFA2_
RecName: Full = A2-
MLSIFETVAAAAPV
1802

USTMA
specific pheromone;
TVAETQQASNNEN



AltName: Full = Mating
RGQPGYYCLIA



factor A2





gi|41209131|gb|AAR99617.1|
lipopeptide mating
SLTYAWCVVA
1803


pheromone precursor




Bap2(3) [ Schizophyllum




commune ]





gi|41209146|gb|AAR99650.1|
lipopeptide mating
TSMAHAWCVVA
1804


pheromone precursor




Bap3(2) [ Schizophyllum




commune ]





gi|41209149|gb|AAR99653.1|
lipopeptide mating
GYCVVA
1805


pheromone precursor




Bbp2(8) [ Schizophyllum




commune ]





gi|46098187|gb|EAK83420.1|
MFA1_USTMA A1-
MLSIFAQTTQTSAS
1806


SPECIFIC PHEROMONE
EPQQSPTAPQGRDN



(MATING FACTOR A1)
GSPIGYSSCVVA



[ Ustilago maydis 521]





gi|546861|gb|AAB30833.1|
M-factor mating
MDSMANTVSSSVV
1807


pheromone
NTGNKPSETLNKT



[ Schizosaccharomyces
VKNYTPKVPYMCV



pombe ]
IA




gi|5917793|gb|AAD56043.1|
pheromone Mfa2
MFSLFETVAAAVK
1808

AF184069_1
[ Ustilago hordei ]
VVSAAEPEHAPTNE




GKGEPAPYCIIA




gi|6014618|gb|AAF01424.1|
Phb3.2.42 [ Coprinus
LTWFCVIA
1809

AF186389_1
cinereus ]





gi|68266363|gb|AAY88882.1|
putative pheromone
LREKRRRRWFEAF
1810


receptor STE3.4
MGFGL



[ Coprinellus disseminatus ]





gi|71012805|ref|XP_758529.1|
A1-specific pheromone
MLSIFAQTTQTSAS
1811


[ Ustilago maydis 521]
EPQQSPTAPQGRDN




GSPIGYSSCVVA




gi|72414834|emb|CAI59748.1|
mating factor a1.3
MDALTLFAPVSLG
1812


[ Sporisorium reilianum ]
AVATEQAPVDEER




PNRQTFPWIGCVV




A




gi|72414854|emb|CAI59758.1|
mating factor a2.1
MFIFESVVASVQAV
1813


[ Sporisorium reilianum ]
SVAEQDQTPVSEG




RGKPAVYCTIA




gi|11275871gbIAAA99767.1|
rba1 gene product
PWMSLLFSFLALLA
1814



LILPKLSKDDPLGL




TRQPR




gi|151941959|gb|EDN60315.1|
pheromone-regulated
ASISLIMEGSANIEA
1815


membraneprotein
VGKLVWLAAALPL



AFI




[ Saccharomyces cerevisiae




YJM789]





gi|3025095|sp907549.1|SNA4_
Protein SNA4
ARNVYPSVETPLLQ
1816

YEAST

GAAPHDNKQSLVE




SPPPYVP




gi|73921293|sp|Q08245.3|ZEO1_
RecName: Full = Protein
FLKKLNRKIASIFN
1817

YEAST
ZEO1; AltName:




Ful1 = Zeocin resistance




protein 1





gi|74644573|sp|Q9P305.3|IGO2_
RecName: Full = Protein
DSISRQGSISSGPPP
1818

YEAST
IGO2
RSPNK



EDF ( E. coli )
NNWNN
1819





































































































































































































































































































































v. Targeting Enhancers/Opsonins
In certain embodiments compositions are contemplated that incorporate a targeting enhancer (e.g., an opsonin) along with one or more targeting moieties (e.g., targeting peptides). Targeting enhancers include moieties that increase binding affinity, and/or binding specificity, and/or internalization of a moiety by the target cell/microorganism.
Accordingly, in certain embodiments, a targeting moiety and/or a targeted antimicrobial molecule comprise a peptide, with the desired level of binding specificity and/or avidity, attached (e.g., conjugated) to an opsonin. When bound to a target cell through the targeting peptide, the opsonin component encourages phagocytosis and destruction by resident macrophages, dendritic cells, monocytes, or PMNs. Opsonins contemplated for conjugation can be of a direct or indirect type.
Direct opsonins include, fore example, any bacterial surface antigen, PAMP (pathogen-associated molecular pattern), or other molecule recognized by host PRRs (pathogen recognizing receptors). Opsonins can include, but are not limited to, bacterial protein, lipid, nucleic acid, charbohydrate and/or oligosaccharide moieties.
In certain embodiments opsonins include, but are not limited to, N-acetyl-D-glucosamine (GlcNAc), N-acetyl-D-galactosamine (GlaNAc), N-acetylglucosamine-containing muramyl peptides, NAG-muramyl peptides, NAG-NAM, peptidoglycan, teichoic acid, lipoteichoic acid, LPS, o-antigen, mannose, fucose, ManNAc, galactose, maltose, glucose, glucosamine, sucrose, mannosamine, galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, or alpha-1,3-gal-gal, or other sugars.
In certain embodiments, opsonins include indirect opsonins. Indirect opsonins function through binding to a direct opsonin already present. For example an Fc portion of an antibody, a sugar-binding lectin protein (example MBL), or host complement factors (example C3b, C4b, iC3b).
In certain embodiments the opsonin is to galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, or alpha-1,3-gal-gal.
Other examples of opsonin molecules include, but are not limited to antibodies (e.g., IgG and IgA), components of the complement system (e.g., C3b, C4b, and iC3b), mannose-binding lectin (MBL) (initiates the formation of C3b), and the like.
Methods of coupling an opsonin to a targeting moiety are well known to those of skill in the art (see, e.g., discussion below regarding attachment of effectors to targeting moieties).
B) Effectors.
Any of a wide number of effectors can be coupled to targeting moieties as described herein to preferentially deliver the effector to a target organism and/or tissue. Illustrative effectors include, but are not limited to detectable labels, small molecule antibiotics, antimicrobial peptides, porphyrins or other photosensitizers, epitope tags/antibodies for use in a pretargeting protocol, agents that physically disrupt the extracellular matrix within a community of microorganisms, microparticles and/or microcapsules, nanoparticles and/or nanocapsules, “carrier” vehicles including, but not limited to lipids, liposomes, dendrimers, cholic acid-based peptide mimics or other peptide mimics, steroid antibiotics, and the like.
i. Detectable Labels.
In certain embodiments chimeric moieties are provided comprising a targeting moiety (e.g., as described in Table 3) attached directly or through a linker to a detectable label. Such chimeric moieties are effective for detecting the presence and/or quantity, and/or location of the microorganism(s) to which the targeting moiety is directed. Similarly these chimeric moieties are useful to identify cells and/or tissues and/or food stuffs and/or other compositions that are infected with the targeted microorganism(s).
Detectable labels suitable for use in such chimeric moieties include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. Illustrative useful labels include, but are not limited to, biotin for staining with labeled streptavidin conjugates, avidin or streptavidin for labeling with biotin conjugates fluorescent dyes (e.g., fluorescein, texas red, rhodamine, green fluorescent protein, and the like, see, e.g., Molecular Probes, Eugene, Oreg., USA), radiolabels (e.g., 3 H, 125 I, 35 S, 14 C, 32 P, 99 Tc, 203 Pb, 67 Ga, 68 Ga, 72 As, 111 In, 113m In, 97 Ru, 62 Cu, 641 Cu, 52 Fe, 52m Mn, 51 Cr, 186 Re, 188 Re, 77 As, 90 Y, 67 Cu, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 199 Au, 161 Tb, 109 Pd, 165 Dy, 149 Pm, 151 Pm, 153 Sm, 157 Gd, 159 Gd, 166 Ho, 172 Tm, 169 Yb, 175 Yb, 177 Lu, 105 Rh, 111 Ag, and the like), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), various colorimetric labels, magnetic or paramagnetic labels (e.g., magnetic and/or paramagnetic nanoparticles), spin labels, radio-opaque labels, and the like. Patents teaching the use of such labels include, for example, U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241.
It will be recognized that fluorescent labels are not to be limited to single species organic molecules, but include inorganic molecules, multi-molecular mixtures of organic and/or inorganic molecules, crystals, heteropolymers, and the like. Thus, for example, CdSe—CdS core-shell nanocrystals enclosed in a silica shell can be easily derivatized for coupling to a biological molecule (Bruchez et al. (1998) Science, 281: 2013-2016). Similarly, highly fluorescent quantum dots (zinc sulfide-capped cadmium selenide) have been covalently coupled to biomolecules for use in ultrasensitive biological detection (Warren and Nie (1998) Science, 281: 2016-2018).
In various embodiments spin labels are provided by reporter molecules with an unpaired electron spin which can be detected by electron spin resonance (ESR) spectroscopy. Illustrative spin labels include organic free radicals, transitional metal complexes, particularly vanadium, copper, iron, and manganese, and the like. Exemplary spin labels include, for example, nitroxide free radicals.
Means of detecting such labels are well known to those of skill in the art. Thus, for example, where the label is a radioactive label, means for detection include a scintillation counter or photographic film as in autoradiography. Where the label is a fluorescent label, it may be detected by exciting the fluorochrome with the appropriate wavelength of light and detecting the resulting fluorescence, e.g., by microscopy, visual inspection, via photographic film, by the use of electronic detectors such as charge coupled devices (CCDs) or photomultipliers and the like. Similarly, enzymatic labels may be detected by providing appropriate substrates for the enzyme and detecting the resulting reaction product. Finally, simple colorimetric labels may be detected simply by observing the color associated with the label.
ii. Antibiotics.
In certain embodiments chimeric moieties are provided comprising a targeting moiety (e.g. as described in Table 3) attached directly or through a linker to a small molecule antibiotic and/or to a carrier (e.g., a lipid or liposome, a polymer, etc.) comprising a small molecule antibiotic. Illustrative antibiotics are shown in Table 13.





TABLE 13



Illustrative antibiotics for use in the chimeric moieties described herein.





Class
Generic Name
BRAND NAME



Aminoglycosides
Amikacin
AMIKIN ®


Gentamicin
GARAMYCIN ®


Kanamycin
KANTREX ®


Neomycin


Netilmicin
NETROMYCIN ®


Streptomycin


Tobramycin
NEBCIN ®


Paromomycin
HUMATIN ®

Carbacephem
Loracarbef
LORABID ®

Carbapenems
Ertapenem
INVANZ ®


Doripenem
FINIBAX ®


Imipenem/Cilastatin
PRIMAXIN ®


Meropenem
MERREM ®

Cephalosporins
Cefadroxil
DURICEF ®

(First generation)
Cefazolin
ANCEF ®


Cefalotin or Cefalothin
KEFLIN ®


Cefalexin
KEFLEX ®

Cephalosporins
Cefaclor
CECLOR ®

(Second
Cefamandole
MANDOLE ®

generation)
Cefoxitin
MEFOXIN ®


Cefprozil
CEFZIL ®


Cefuroxime
CEFTIN, ZINNAT ®

Cephalosporins
Cefixime
SUPRAX ®

(Third
Cefdinir
OMNICEF ®

generation)
Cefditoren
SPECTRACEF ®


Cefoperazone
CEFOBID ®


Cefotaxime
CLAFORAN ®


Cefpodoxime


Ceftazidime
FORTAZ ®


Ceftibuten
CEDAX ®


Ceftizoxime


Ceftriaxone
ROCEPHIN ®

Cephalosporins
Cefepime
MAXIPIME ®

(Fourth

generation)

Cephalosporins
Ceftobiprole

(Fifth generation)

Glycopeptides
Teicoplanin


Vancomycin
VANCOCIN ®

Macrolides

Azithromycin
Zithromax

Clarithromycin
Biaxin

Dirithromycin

Erythromycin
Erythocin, Erythroped

Roxithromycin

Troleandomycin

Telithromycin
Ketek

Monobactams
Aztreonam

Penicillins
Amoxicillin
NOVAMOX ®, AMOXIL ®


Ampicillin


Azlocillin


Carbenicillin


Cloxacillin


Dicloxacillin


Flucloxacillin
FLOXAPEN ®


Mezlocillin


Meticillin


Nafcillin


Oxacillin


Penicillin


Piperacillin


Ticarcillin

Polypeptides
Bacitracin


Colistin


Polymyxin B

Quinolones
Mafenide


Prontosil (archaic)


Sulfacetamide


Sulfamethizole


Sulfanilimide (archaic)


Sulfasalazine


Sulfisoxazole


Trimethoprim
BACTRIM ®


Trimethoprim-


Sulfamethoxazole (Co-


trimoxazole)


(TMP-SMX)

Tetracyclines
Demeclocycline


Doxycycline
VIBRAMYCIN ®


Minocycline
MINOCIN ®


Oxytetracycline
TERRACIN ®


Tetracycline
SUMYCIN ®

Natural products
Antimicrobial herbal


extracts


Essential oils


Farnesol


Licorice root extracts


Glycyrrhizol A


Glycyrrhizol B


6,8-diisoprenyl-5,7,4′-


trihydroxyisoflavone

Others
Arsphenamine
SALVARSAN ®


Chloramphenicol
CHLOROMYCETIN ®


Clindamycin
CLEOCIN ®


Lincomycin


Ethambutol


Fosfomycin


Fusidic acid
FUCIDIN ®


Furazolidone


Isoniazid


Linezolid
ZYVOX ®


Metronidazole
FLAGYL ®


Mupirocin
BACTROBAN ®


Nitrofurantoin
MACRODANTIN ®,



MACROBID ®


Platensimycin


Pyrazinamide


Quinupristin/
SYNCERCID ®


Dalfopristin


Rifampin or


Rifampicin


Tinidazole


Artemisinin

Antifungals
Amphotericin B


Anidulafungin


Caspofungin acetate


Clotrimazole


Fluconazole


Flucytosine


Griseofulvin


Itraconazole


Ketoconazole


Micafungin


Miconazole


Nystatin


Pentamidine


Posaconazole


Terbinafine


Voriconazole

Antimycobiotics
Aminosalicylic Acid


Capreomycin


Clofazimine


Cycloserine


Ethionamide


Rifabutin


Rifapentine

Antivirals
Abacavir


Acyclovir


Adefovir


Amantadine


Atazanavir


Cidofovir


Darunavir


Didanosine


Docosanol


Efavirenz


Emtricitabine


Enfuvirtide


Entecavir


Etravirine


Famciclovir


Fomivirsen


Fosamprenavir


Foscarnet


Ganciclovir


Idoxuridine


Indinavir


Interferon alpha


Lamivudine


Lopinavir/ritonavir


Maraviroc


Nelfinavir


Nevirapine


Oseltamivir


Penciclovir


Peramivir


Raltegravir


Ribavirin


Rimantadine


Ritonavir


Saquinavir


Stavudine


Telbivudine


Tenofovir


Tipranavir


Trifluridine


Valacyclovir


Valganciclovir


Zanamivir


Zidovudine

Anti-parasitics
Albendazole


Artesunate


Atovaquone


Bephenium


hydroxynaphthoate


Chloroquine


Dapsone


Diethyl-carbamazine


Diloxanide furoate


Eflornithine


Emetine HCl


Furazolidone


Ivermectin


Lindane


Mebendazole


Mefloquine


Melarsoprol


Miltefosine


Niclosamide


Nifurtimox


Nitazoxanide


Oxamniquine


Paromomycin


Permethrin


Piperazine


Praziquantel


Primaquine


Pyrantel pamoate


Pyrimethamine


Proguanil


Quinacrine HCl


Quinidine


Quinine


Sodium Stibogluconate


Spiramycin


Thiabendazole


Tinidazole













































































































































































































































iii. Porphyrins and Non-Porphyrin Photosensitizers.
In certain embodiments, porphyrins and other photosensitizers can be used as targeting moieties and/or as effectors in the methods and compositions of this invention. A photosensitizer is a drug or other chemical that increases photosensitivity of the organism (e.g., bacterium, yeast, fungus, etc.). As targeting moieties the photosensitizers (e.g., porphyrins) are preferentially uptaken by the target microorganisms and thereby facilitate delivery of the chimeric moiety to the target microorganism.
As effectors, photosensitizers can be useful in photodynamic antimicrobial chemotherapy (PACT). In various embodiments PACT utilizes photosensitizers and light (e.g., visible, ultraviolet, infrared, etc.) in order to give a phototoxic response in the target organism(s), often via oxidative damage.
Currently, the major use of PACT is in the disinfection of blood products, particularly for viral inactivation, although more clinically-based protocols are used, e.g. in the treatment of oral infection or topical infection. The technique has been shown to be effective in vitro against bacteria (including drug-resistant strains), yeasts, viruses, parasites, and the like.
Attaching a targeting moiety (e.g., a targeting peptide) to the photosensitizer, e.g., as described herein, provides a means of specifically or preferentially targeting the photosensitizer(s) to particular species or strains(s) of microorganism.
A wide range of photosensitizers, both natural and synthetic are known to those of skill in the art (see, e.g., Wainwright (1998) J. Antimicrob. Chemotherap. 42: 13-28). Photosensitizers are available with differing physicochemical make-up and light-absorption properties. In various embodiments photosensitizers are usually aromatic molecules that are efficient in the formation of long-lived triplet excited states. In terms of the energy absorbed by the aromatic-system, this again depends on the molecular structure involved. For example, furocoumarin photosensitizers (psoralens) absorb relatively high energy ultraviolet (UV) light (c. 300-350 nm), whereas macrocyclic, heteroaromatic molecules such as the phthalocyanines absorb lower energy, near-infrared light.
Illustrative photosensitizers include, but are not limited to porphyrinic macrocyles (especially porphyrins, chlorines, etc., see, e.g., FIGS. 1 and 2 ). In particular, metalloporphyrins, particularly a number of non-iron metalloporphyrins mimic haem in their molecular structure and are actively accumulated by bacteria via high affinity haem-uptake systems. The same uptake systems can be used to deliver antibiotic-porphyrin and antibacterial-porphyrin conjugates. Illustrative targeting porphyrins suitable for this purpose are described in U.S. Pat. No. 6,066,628 and shown herein in FIGS. 1 and 2 .
Illustrative examples of targeted porphyrins are described in Example 5 and associated figures and in FIG. 13 .
For example, certain artificial (non-iron) metalloporphyrins (MPs) (Ga-IX, Mn-IX,) are active against Gram-negative and Gram-positive bacteria and acid-fast bacilli (e.g., Y. enterocolitica, N. meningitides, S. marcescens, E. coli, P. mirabilis, K pneumoniae, K. oxytoca, Ps. aeruginosa, C. freundii, E. aerogenes, F. menigosepticum, S. aureus, B. subtilis, S. pyogenes A, E. faecalis, M. smegmatis, M. bovis, M. tuber., S. crevisiae ) as described in Tables 1-5 of U.S. Pat. No. 6,066,628. These MPs can be used as targeting moieties against these microorganisms.
Similarly, some MPs are also growth-inhibitory against yeasts, indicating their usefulness targeting moieties to target Candida species (e.g., Candida albicans, C. krusei, C. pillosus, C. glabrata , etc.) and other mycoses including but not limited to those caused by as Trichophyton, Epidermophyton, Histoplasma, Aspergillus, Cryptococcus , and the like.
Other photosensitizers include, but are not limited to cyanines (see, e.g., FIG. 6 ) and phthalocyanines (see, e.g., FIG. 4 ), azines (see, e.g., FIG. 5 ) including especially methylene blue and touidine blue, hypericin (see, e.g., FIG. 8 ), acridines (see, e.g., FIG. 9 ) including especially Rose Bengal (see, e.g., FIG. 10 ), crown ethers (see, e.g., FIG. 11 ), and the like. In certain embodiments, the photosensitizers include tin chlorin 6 and related compounds (e.g., other chlorines and tin porphyrins).
Another light-activated compound is cucumin (see, FIG. 12 ).
In certain embodiments the photosensitizers are toxic or growth inhibitors without light activation. For example, some non-iron metalloporphyrins (MPs) (see, e.g., FIGS. 1 and 2 herein) possess a powerful light-independent antimicrobial activity. In addition, haemin, the most well known natural porphyrin, possesses a significant antibacterial activity that can augmented by the presence of physiological concentrations of hydrogen peroxide or a reducing agent.
Typically, when activated by light, the toxicity or growth inhibition effect is substantially increased. Typically, they generate radical species that affect anything within proximity. In certain embodiments to get the best selectivity from targeted photosensitizers, anti-oxidants can be used to quench un-bound photosensitizers, limiting the damage only to cells where the conjugates have accumulated due to the targeting peptide. The membrane structures of the target cell act as the proton donors in this case.
In typical photodynamic antimicrobial chemotherapy (PACT) the targeted photosensitizer is “activated by the application of a light source (e.g., a visible light source, an ultraviolate light source, an infrared light source, etc.). PACT applications however need not be limited to topical use. Regions of the mouth, throat, nose, sinuses are readily illuminated. Similarly regions of the gut can readily be illuminated using endoscopic techniques. Other internal regions can be illumined using laparoscopic methods or during other surgical procedures. For example, in certain embodiments involving the insertion or repair or replacement of an implantable device (e.g., a prosthetic device) it contemplated that the device can be coated or otherwise contacted with a chimeric moiety comprising a targeting moiety attached to a photosensitizer as described herein. During the surgical procedure and/or just before closing, the device can be illuminated with an appropriate light source to activate the photosensitizer.
The targeted photosensitizers and uses thereof described herein are illustrative and not to be limiting. Using the teachings provided herein, other targeted photosensitizers and uses thereof will be available to one of skill in the art.
iv. Antimicrobial Peptides.
In certain embodiments, the effector can comprise one or more antimicrobial peptides or compound antimicrobial peptides, e.g., as described above. Numerous antimicrobial peptides are well known to those of skill in the art.
In certain embodiments the antimicrobial peptides comprise one or more amino acid sequences described above (e.g., one or more domains comprising amino acid sequences in Tables 4 and/or 5) and/or one or more of the amino acid sequences shown in Table 14. In certain embodiments the antimicrobial peptides comprise one or more amino acid sequences described in the “Collection of Anti-Microbial Peptides” (CAMP) an online database developed for advancement the understanding of antimicrobial peptides (see, e.g., Thomas et al. (2009) Nucleic Acids Research, 2009, 1-7.doi:10.1093/nar/gkp1021) available at www.bicnirrh.res.in/antimicrobial.





TABLE 14



Other illustrative antimicrobial peptides. AP numbers refer to ID in

antimicrobial peptide database (http://aps.unmc.edu/AP/main.php).









SEQ ID


Effector
Structure/Sequence
No



AP00274
1BH4, Circulin A
GIPCGESCVWIPCISAALGCSCKNK
1820


(CirA, plant
VCYRN



cyclotides,XXC,




ZZHp)





AP00036
1BNB, Beta-
DFASCHTNGGICLPNRCPGHMIQIG
1821


defensin 1 (cow)
ICFRPRVKCCRSW




AP00047
1BNB, Bovine
GPLSCGRNGGVCIPIRCPVPMRQIG
1822


neutrophil beta-
TCFGRPVKCCRSW



defensin 12




(BNBD-12, cow)





AP00428
1C01, MiAMP1
SAFTVWSGPGCNNRAERYSKCGCS
1823


(Macadamia
AIHQKGGYDFSYTGQTAALYNQA



integrifolia
GCSGVAHTRFGSSARACNPFGWKS



antimicrobial
IFIQC



peptide 1, plant)





AP00154
1CIX, Tachystatin
YSRCQLQGFNCVVRSYGLPTIPCC
1824


A2 (Horseshoe
RGLTCRSYFPGSTYGRCQRY



crabs, Crustacea,




BBS)





AP00145
1CW5,
VNYGNGVSCSKTKCSVNWGQAFQ
1825


Carnobacteriocin
ERYTAGINSFVSGVASGAGSIGRRP



B2 (CnbB2, class




IIA




bacteriocin, bacteria)





AP00153
1CZ6, Androctonin
RSVCRQIKICRRRGGCYYKCTNRP
1826


(scorpions)
Y




AP00152
1D6X, Tritrpticin
VRRFPWWWPFLRR
1827


(synthetic)





AP00201
1D7N, Mastoparan
INLKALAALAKKIL
1828


(insect)





AP00140
1D9J, CecropinA-
KWKLFKKIGIGKFLHSAKKF
1829


Magainin2 hybrid




(synthetic)





AP00178
1DFN, human
DCYCRIPACIAGERRYGTCIYQGRL
1830


alpha Defensin
WAFCC



HNP-3 (human




neutrophil peptide-




3, HNP3, human




defensin, ZZHh)





AP01153
1DQC, Tachycitin
YLAFRCGRYSPCLDDGPNVNLYSC
1831


(horseshoe crabs,
CSFYNCHKCLARLENCPKGLHYN



Crustacea, BBS)
AYLKVCDWPSKAGCT




AP00437
1DUM, Magainin 2
GIGKYLHSAKKFGKAWVGEIMNS
1832


analog (synthetic)





AP00451
1E4S, Human beta
DHYNCVSSGGQCLYSACPIFTKIQG
1833


defensin 1 (HBD-1,
TCYRGKAKCCK



human
defensin)




AP00149
1EWS, Rabbit
NIPCSCKKYCDPWEVIDGSCGLFNS
1834


kidney defensin 1
KYICCREK



(RK-1)





AP00141
1F0E, CecropinA-
KWKLFKKIPKFLHSAKKF
1835


Magainin2 Hybrid




(P18, synthetic)





AP00142
1F0G, CecropinA-
KLKLFKKIGIGKFLHSAKKF
1836


Magainin2 Hybrid




(synthetic)





AP00143
1FOH, CecropinA-
KAKLFKKIGIGKFLHSAKKF
1837


Magainin2 Hybrid




(synthetic)





AP00524
1FD4, Human beta
GIGDPVTCLKSGAICHPVFCPRRYK
1838


defensin 2 (HBD-2,
QIGTCGLPGTKCCKKP



human defensin,




ZZHh)





AP00438
1FJN, Mussel
GFGCPNNYQCHRHCKSIPGRCGGY
1839


Defensin MGD-1
CGGWHRLPCTCYRCG




AP00155
1FRY, SMAP-29
RGLRRLGRKIAHGVKKYGPTVLRII
1840


(SMAP29, sheep
RIAG



cathelicidin)





AP00150
1G89, Indolicidin
ILPWKWPWWPWRR
1841


(cow cathelicidin,




BBN, ZZHa)





AP00156
1GR4, Microcin
VGIGTPISFYGGGAGHVPEYF
1842


J25, linear




(MccJ25,




bacteriocin,




bacteria)





AP00151
1HR1, Indolicidin
ILAWKWAWWAWRR
1843


P to A mutant




(synthetic)





AP00196
1HU5, Ovispirin-1
KNLRRIIRKIIHIIKKYG
1844


(synthetic)





AP00197
1HU6, Novispirin
KNLRRIIRKGIHIIKKYG
1845


G10 (synthetic)





AP00198
1HU7, Novispirin
KNLRRITRKIIHIIKKYG
1846


T7 (synthetic)





AP00445
1HVZ, Monkey
GFCRCLCRRGVCRCICTR
1847


RTD-1 (rhesus




theta-defensin-1,




minidefensin-1,




animal defensin,




XXC, BBS, lectin,




ZZHa)





AP00103
li2v, Heliomicin
DKLIGSCVWGAVNYTSDCNGECL
1848


variant (Hel-LL,
LRGYKGGHCGSFANVNCWCET



synthetic)





AP00216
lICA, Phormia
ATCDLLSGTGINHSACAAHCLLRG
1849


defensin A (insect
NRGGYCNGKGVCVCRN



defensin A)





AP01224
1Jo3, Gramicidin B
VGALAVVVWLFLWLW
1850


(bacteria)





AP01225
ljo4, Gramicidin C
VGALAVVVWLYLWLW
1851


(bacteria)





AP00191
1KFP, Gomesin
ECRRLCYKQRCVTYCRGR
1852


(Gm, Spider, XXA)





AP00283
1KJ6, Huamn beta
GIINTLQKYYCRVRGGRCAVLSCL
1853


defensin 3 (HBD-3,
PKEEQIGKCSTRGRKCCRRKK



human defensin,




ZZHh)





AP00147
1KV4, Moricin
AKIPIKAIKTVGKAVGKGLRAINIA
1854


STAND
VFNFLKPKKRKA



(insect, silk moth)





AP00227
1L4V, Sapecin
ATCDLLSGTGINHSACAAHCLLRG
1855


(insect, flesh fly)
NRGGYCNGKAVCVCRN




AP01161
1L9L, Human
GRDYRTCLTIVQKLKKMVDKPTQ
1856


granulysin
RSVSNAATRVCTRGRSRWRDVCR



(huGran)
NFMRRYQSRVIQGLVAGETAQQIC




EDLRLCIPSTGPL




AP00026
1LFC,
FKCRRWQWRMKKLGAPSITCVRR
1857


Lactoferricin B
AF



(LfcinB, cow,




ZZHa)





AP00193
1M4F, human
DTHFPICIFCCGCCHRSKCGMCCKT
1858


LEAP-1 (Hepcidin




25)





AP00499
1MAG, Gramicidin
VGALAVVVWLWLWLW
1859


A (gA, bacteria)





AP00403
1MM0, Termicin
ACNFQSCWATCQAQHSIYFRRAFC
1860


(termite defensin,
DRSQCKCVFVRG



insect defensin)





AP00194
1MMC, Ac-AMP2
VGECVRGRCPSQFGYCGKSGMCC
1861


(plant defensin,
GPKYCGR



BBS)





AP01206
1MQZ, Mersacidin
CTFTLPGGGGVCTLTSECIC
1862


(bacteria)





AP00429
1NKL, Porcine
GYFCESCRKIIQKLEDMVGPQPNE
1863


NK-Lysin (pig)
DTVTQAASQVCDKLKILRGLCKKI




IVIRSFLRRISWDILTGKKPQAICVDI




KICKE




AP00633
log7, Sakacin P/
KYYGNGVHCGKHSCTVDWGTAIG
1864


Sakacin 674 (SakP,
NIGNNAAANWATGGNAGWNK



class IIA




bacteriocin,




bacteria)





AP00195
1PG1, Protegrin 1
RGGRLCYCRRRFCVCVGR
1865


(Protegrin-1, PG-1,




pig cathelicidin,




XXA, ZZHa,




BBBm)





AP00928
1PXQ, Subtilosin
NKGCATCSIGAACLVDGPIPDFEIA
1866


A (XXC, class I
GATGLFGLWG



bacteriocin, Gram-




positive bacteria)





AP00480
1Q71, Microcin
VGIGTPIFSYGGGAGHVPEYF
1867


J25 (cyclic




MccJ25, class I




microcins,




bacteriocins, Gram-




negative bacteria,




XXC; BBP)





AP00211
1RKK,
RRWCFRVCYRGFCYRKCR
1868


Polyphemusin I




(crabs, Crustacea)





AP00430
1T51, IsCT
ILGKIWEGIKSLF
1869


(Scorpion)





AP00731
1ut3, Spheniscin-2
SFGLCRLRRGFCARGRCRFPSIPIGR
1870


(Sphe-2, penguin
CSRFVQCCRRVW



defensin, avian




defensin)





AP00013
1VM5, Aurein 1.2
GLFDIIKKIAESF
1871


(frog)





AP00214
1WO1,
KWCFRVCYRGICYRRCR
1872


Tachyplesin I




(crabs, Crustacea,




XXA, ZZHa)





AP00644
lxc0, Pardaxin 4
GFFALIPKIISSPLFKTLLSAVGSALS
1873


(Pardaxin P-4,
SSGGQE



Pardaxin P4, Pa4,




flat fish)





AP00493
1XKM, Distinctin
NLVSGLIEARKYLEQLHRKLKNCK
1874


(two chains for
V



stability and




transport frog)





AP00420
1XV3, Penaeidin-
HSSGYTRPLRKPSRPIFIRPIGCDVC
1875


4d (penaeidin 4,
YGIPSSTARLCCFRYGDCCHL



shrimp, Crustacea)





AP00035
lYTR, Plantaricin
KSSAYSLQMGATAIKQVKKLFKK
1876


A (PlnA,
WGW



bacteriocin,




bacteria)





AP00166
1Z64, Pleurocidin
GWGSFFKKAAHVGKHVGKAALT
1877


(fish)
HYL




AP00780
1Z6V, Human
GRRRRSVQWCAVSQPEATKCFQW
1878


lactoferricin
QRNMRKVRGPPVSCIKRDSPIQCIQ




A




AP00549
1ZFU, Plectasin
GFGCNGPWDEDDMQCHNHCKSIK
1879


(fungi, fungal
GYKGGYCAKGGFVCKCY



defensin)





AP00177
IZMH, human
CYCRIPACIAGERRYGTCIYQGRL
1880


alpha Defensin
WAFCC



HNP-2 (human




neutrophil peptide-




2, HNP2, human




defensin, ZZHh)





AP00179
1ZMM, human
VCSCRLVFCRRTELRVGNCLIGGV
1881


alpha Defensin
SFTYCCTRVD



HNP-4 (human




neutrophil peptide-




4, HNP4, human




defensin)





AP00180
1ZMP, human
QARATCYCRTGRCATRESLSGVCE
1882


alpha Defensin
ISGRLYRLCCR



HD-5 (HD5,




human
defensin)




AP00181
1ZMQ, human
STRAFTCHCRRSCYSTEYSYGTCT
1883


alpha Defensin
VMGINHRFCCL



HD-6 (HD6,




human
defensin)




AP00399
1ZRW, Spinigerin
HVDKKVADKVLLLKQLRIMRLLT
1884


(insect, termite)
RL




AP01157
1ZRX, Stomoxyn
RGFRKHFNKLVKKVKHTISETAHV
1885


(insect)
AKDTAVIAGSGAAVVAAT




AP00637
2A2B, Curvacin A/
ARSYGNGVYCNNKKCWVNRGEA
1886


sakacin A (CurA,
TQSIIGGMISGWASGLAGM



SakA, class IIA




bacteriocin,




bacteria)





AP00558
2B68, Cg-Def
GFGCPGNQLKCNNHCKSISCRAGY
1887


(Crassostrea gigas
CDAATLWLRCTCTDCNGKK



defensin, oyster




defensin, animal




defensin)





AP01154
2B9K, LCI
AIKLVQSPNGNFAASFVLDGTKWI
1888


(bacteria)
FKSKYYDSSKGYWVGIYEVWDRK




AP01005
2DCV, Tachystatin
YVSCLFRGARCRVYSGRSCCFGYY
1889


B1 (BBS,
CRRDFPGSIFGTCSRRNF



horseshoe crabs)





AP01006
2DCW,
YITCLFRGARCRVYSGRSCCFGYY
1890


Tachystatin B1
CRRDFPGSIFGTCSRRNF



(BBS, horseshoe




crabs)





AP00275
2ERI, Circulin B
CGESCVFIPCISTLLGCSCKNKVCY
1891


(CirB, plant
RNGVIP



cyclotides,XXC,




ZZHp)





AP00707
2f3a, LLAA (LL-
RLFDKIRQVIRKF
1892


37-derived aurein




1.2 analog, retro-




FK13, synthetic)





AP00708
2fbs, FK-13 (FK13,
FKRIVQRIKDFLR
1893


NMR-discovered




LL-37 core peptide,




XXA, ZZHs,




synthetic)





AP00088
2G9L, Gaegurin-4
GILDTLKQFAKGVGKDLVKGAAQ
1894


(Gaegurin 4, frog)
GVLSTVSCKLAKTC




AP01011
2G9P, Latarcin 2a
GLFGKLIKKFGRKAISYAVKKARG
1895


(Ltc2a, BBM,
KH



spider)





AP00612
2GDL, Fowlicidin-
LVQRGRFGRFLRKIRRFRPKVTITI
1896


2 (chCATH-2, bird
QGSARFG



cathelicidin,




chicken




cathelicidin, BBL)





AP00402
2GL1, VrD2
KTCENLANTYRGPCFTTGSCDDHC
1897


(Vigna radiata
KNKEHLRSGRCRDDFRCWCTRNC



defensin 2, plant




defensin, mung




bean)





AP00285
2GW9, Cryptdin-4
GLLCYCRKGHCKRGERVRGTCGIR
1898


(Crp4, animal
FLYCCPRR



defensin, alpha,




mouse)





AP00613
2hfr, Fowlicidin-3
RVKRFWPLVPVAINTVAAGINLYK
1899


(chCATH-3, bird
AIRRK



cathelicidin,




chicken




cathelicidin)





AP01007
2JMY, CM15
KWKLFKKIGAVLKVL
1900


(Synthetic)





AP00728
2jni, Arenicin-2
RWCVYAYVRIRGVLVRYRRCW
1901


(marine polychaeta,




BBBm)





AP00473
2j0s, Piscidin 1
FFHHIFRGIVHVGKTIHRLVTG
1902


(fish)





AP01151
2JPJ, Lactococcin
GTWDDIGQGIGRVAYWVGKALGN
1903


G-a (chain a, class
LSDVNQASRINRKKKH



IIb bacteriocin,




bacteria. For chain




b, see info)





AP00757
2jpy, Phylloseptin-
FLSLIPHAINAVSTLVHHF
1904


H2 (PLS-H2,




Phylloseptin-2, PS-




2) (XXA, frog)





AP00546
2jq0, Phylloseptin-
FLSLIPHAINAVSAIAKHN
1905


1 (Phylloseptin-H1,




PLS-H1, PS-1,




XXA, frog)





AP00758
2jq1, Phylloseptin-
FLSLIPHAINAVSALANHG
1906


3 (Phylloseptin-H3,




PLS-H3, PS-3)




(XXA, frog)





AP00727
2jsb, Arenicin-1
RWCVYAYVRVRGVLVRYRRCW
1907


(marine polychaeta,




BBBm)





AP00592
2k10, Ranatuerin-
GILSSFKGVAKGVAKDLAGKLLET
1908


2CSa (frog)
LKCKITGC




AP00485
2K38, Cupiennin
GFGALFKFLAKKVAKTVAKQAAK
1909


1a (spider)
QGAKYVVNKQME




AP00310
2K6O, Human LL-
LLGDFFRKSKEKIGKEFKRIVQRIK
1910


37 (LL37, human
DFLRNLVPRTES



cathelicidin;




released by




proteinase 3 from




its precursor in




neutrophils; FALL-




39; BBB, BBM,




BBP, BBW, BBD,




BBL, ZZHh)





AP00199
2LEU, Leucocin A
KYYGNGVHCTKSGCSVNWGEAFS
1911


(LeuA, class Ha
AGVHRLANGGNGFW



bacteriocin,




bacteria)





AP00144
2MAG, Magainin 2
GIGKFLHSAKKFGKAFVGEIMNS
1912


(frog)





AP00146
2MLT, Melittin
GIGAVLKVLTTGLPALISWIKRKRQ
1913


(insect, ZZHa)
Q




AP01010
2PCO, Latarcin 1
SMWSGMWRRKLKKLRNALKKKL
1914


(Ltc1, BBM,
KGEK



spider)





AP00176
2PM1, human
ACYCRIPACIAGERRYGTCIYQGRL
1915


alpha Defensin
WAFCC



HNP-1 (human




neutrophil peptide-




1, HNP1, human




defensin, ZZHh)





AP01158
2RLG, RP-1
ALYKKFKKKLLKSLKRL
1916


(synthetic)





AP00102
8TFV, Thanatin
GSKKPVPHYCNRRTGKCQRM
1917


(insect)





AP00995
A58718, Carnocin
GSEIQPR
1918


UI49 (bacteria)





AP01002
AAC18827,
KSWSLCTPGCARTGSFNSYCC
1919


Mutacin III




(mutacin 1140,




bacteria)





AP00987
ABI74601, Arasin
SRWPSPGRPRPFPGRPKPIFRPRPCN
1920


1 (Crustacea)
CYAPPCPCDRW




AP01000
CAA63706,
GSGVIPTISHECHMNSFQFVFTCCS
1921


variacin




(lantibiotic, class I




bacteriocin,




bacteria)





AP00361
O15946, Lebocin 4
DLRFWNPREKLPLPTLPPFNPKPIYI
1922


(insect, silk moth)
DMGNRY




AP00343
O16825, Andropin
VFIDILDKMENAIHKAAQAGIGIAK
1923


(insect, fruit fly)
PIEKMILPK




AP00417
O17513,
SIGTAVKKAVPIAKKVGKVAIPIAK
1924


Ceratotoxin D
AVLSVVGQLVG



(insect, fly)





AP00435
O18494, Styelin C
GWFGKAFRSVSNFYKKHKTYIHA
1925


(sea squirt,
GLSAATLL



tunicate, XXA)





AP00330
O18495, Styelin D
GWLRKAAKSVGKFYYKHKYYIKA
1926


(Sea squirt,
AWQIGKHAL



tunicate, XXA)





AP00331
O18495, Styelin E
GWLRKAAKSVGKFYYKHKYYIKA
1927


(Sea squirt,
AWKIGRHAL



tunicate, XXA)





AP01001
O54329, Mutacin II
NRWWQGVVPTVSYECRMNSWQH
1928


(lantibiotic,
VFTCC



mutacin H-29B, J-




T8, class I




bacteriocin,




bacteria)





AP00342
O81338,
AKCIKNGKGCREDQGPPFCCSGFC
1929


Antimicrobial
YRQVGWARGYCKNR



peptide 1 (plant)





AP00373
O96059, Moricin 2
AKIPIKAIKTVGKAVGKGLRAINIA
1930


(insect)
STANDVFNFLKPKKRKH




AP00449
P01190,
SYSMEHFRWGKPV
1931


Melanotropin alpha




(Alpha-MSH)





AP00187
P01376,
VVCACRRALCLPRERRAGFCRIRG
1932


CORTICOSTATIN
RIHPLCCRR



III (MCP-1, rabbit




neutrophil peptide




1, NP-1) (animal




defensin, alpha-




defensin, rabbit)





AP00188
P01377,
VVCACRRALCLPLERRAGFCRIRG
1933


CORTICOSTATIN
RIHPLCCRR



IV ( MCP-2, rabbit




neutrophil defensin




2, NP-2, animal




defensin, rabbit)





AP00049
P01505, Bombinin
GIGALSAKGALKGLAKGLAEHFAN
1934


(toad)





AP00139
P01507, Cecropin
KWKLFKKIEKVGQNIRDGIIKAGP
1935


A (insect, ZZHa)
AVAVVGQATQIAK




AP00128
P01509, Cecropin
KWKIFKKIEKVGRNIRNGIIKAGPA
1936


B (insect, silk
VAVLGEAKAL



moth)





AP00131
P01511, Cecropin
WNPFKELERAGQRVRDAIISAGPA
1937


D (insect, moth)
VATVAQATALAK




AP00136
P01518, Crabrolin
FLPLILRKIVTAL
1938


(insect, XXA)





AP00183
P04142, Cecropin
RWKIFKKIEKMGRNIRDGIVKAGP
1939


B (insect)
AIEVLGSAKAI




AP00448
P04205,
INLKAIAALAKKLL
1940


Mastoparan M




(MP-M, insect,




XXA)





AP00234
P06833,
SDEKASPDKHHRFSLSRYAKLANR
1941


Seminalplasmin
LANPKLLETFLSKWIGDRGNRSV



(SPLN, calcium




transporter




inhibitor, caltrin,




cow)





AP00314
P07466, Rabbit
VFCTCRGFLCGSGERASGSCTINGV
1942


neutrophil peptide
RHTLCCRR



5 (NP-5, animal




defensin, alpha-




defensin)





AP00189
P07467, Rabbit
VSCTCRRFSCGFGERASGSCTVNG
1943


neutrophil peptide
VRHTLCCRR



4 (NP-4)





AP00186
P07468,
GRCVCRKQLLCSYRERRIGDCKIR
1944


CORTICOSTATIN
GVRFPFCCPR



II (Rabbit




neutrophil peptide




3b (NP-3b, rabbit)





AP00185
P07469,
ICACRRRFCPNSERFSGYCRVNGA
1945


CORTICOSTATIN
RYVRCCSRR



I (rabbit)





AP00217
P07469, Rabbit
GICACRRRFCPNSERFSGYCRVNG
1946


neutrophil defensin
ARYVRCCSRR



3a (NP-3a, animal




defensin, alpha-




defensin)





AP00067
P07493,
SKITDILAKLGKVLAHV
1947


Bombolitin II




(insect, bee)





AP00068
P07494,
IKIMDILAKLGKVLAHV
1948


Bombolitin III




(insect, bee)





AP00069
P07495,
INIKDILAKLVKVLGHV
1949


Bombolitin IV




(insect, bee)





AP00070
P07496,
INVLGILGLLGKALSHL
1950


Bombolitin V




(insect, bee)





AP00236
P07504, Pyrularia
KSCCRNTWARNCYNVCRLPGTISR
1951


thionin (Pp-TH,
EICAKKCDCKIISGTTCPSDYPK



plant)





AP00230
P08375, Sarcotoxin
GWLKKIGKKIERVGQHTRDATIQG
1952


IA (insect, flesh
LGIAQQAANVAATAR




AP00231
P08376, Sarcotoxin
GWLKKIGKKIERVGQHTRDATIQV
1953


IB (insect, flesh
IGVAQQAANVAATAR




AP00232
P08377, Sarcotoxin
GWLRKIGKKIERVGQHTRDATIQV
1954


IC (insect, flesh
LGIAQQAANVAATAR




AP00066
P10521,
IKITTMLAKLGKVLAHV
1955


Bombolitin I




(insect, bee)





AP00206
P10946, Lantibiotic
WKSESLCTPGCVTGALQTCFLQTL
1956


subtilin (class I
TCNCKISK



bacteriocin,




bacteria)





AP00312
P11477, Cryptdin-2
LRDLVCYCRARGCKGRERMNGTC
1957


(Crp2, animal
RKGHLLYMLCCR



defensin, alpha,




mouse)





AP00205
P13068, Nisin A
ITSISLCTPGCKTGALMGCNMKTA
1958


(lantibiotic, class I
TCHCSIHVSK



bacteriocin,




bacteria)





AP00215
P14214,
RWCFRVCYRGICYRKCR
1959


Tachyplesin II




(crabs, Crustacea)





AP00212
P14216,
RRWCFRVCYKGFCYRKCR
1960


Polyphemusin II




(crabs, Crustacea,




XXA, ZZHa.




Derivatives: T22)





AP00134
P14661, Cecropin
SWLSKTAKKLENSAKKRISEGIAIA
1961


P1 (pig)
IQGGPR




AP00011
P14662,
WNPFKELERAGQRVRDAVISAAPA
1962


Bactericidin B2
VATVGQAAAIARG



(insect)





AP00032
P14663,
WNPFKELERAGQRVRDAIISAGPA
1963


Bactericidin B-3
VATVGQAAAIARG



(insect)





AP00033
P14664,
WNPFKELERAGQRVRDAIISAAPA
1964


Bactericidin B-4
VATVGQAAAIARG



(insect)





AP00034
P14665,
WNPFKELERAGQRVRDAVISAAA
1965


Bactericidin B-5P
VATVGQAAAIARG



(insect)





AP00125
P14666, Cecropin
RWKIFKKIEKVGQNIRDGIVKAGP
1966


(insect, silk moth)
AVAVVGQAATI




AP00002
P15450,
YVPLPNVPQPGRRPFPTFPGQGPFN
1967


ABAECIN
PKIKWPQGY



(insect,




honeybee)





AP00505
P15516, human
DSHAKRHHGYKRKFHEKHHSHRG
1968


Histatin 5 (ZZHs;
Y



derivatives Dh-5)





AP00520
P15516, human
DSHAKRHHGYKRKFHEKHHSHRG
1969


Histatin 3
YRSNYLYDN




AP00523
P15516, human
KFHEKHHSHRGY
1970


Histatin 8





AP00226
P17722, Royalisin
VTCDLLSFKGQVNDSACAANCLSL
1971


(insect, honeybee)
GKAGGHCEKVGCICRKTSFKDLW




DKRF




AP00213
P18252,
KWCFRVCYRGICYRKCR
1972


Tachyplesin III




(horseshoe crabs,




Crustacea)





AP00233
P18312, Sarcotoxin
GWIRDFGKRIERVGQHTRDATIQTI
1973


ID (insect, flesh
AVAQQAANVAATLKG




AP00207
P19578, Lantibiotic
TAGPAIRASVKQCQKTLKATRLFT
1974


PEPS (class I
VSCKGKNGCK



bacteriocin,




bacteria)





AP00009
P19660,
RFRPPIRRPPIRPPFYPPFRPPIRPPIF
1975


BACTENECIN 5
PPIRPPFRPPLGPFP



(bac5, cow




cathelicidin)





AP00010
P19661,
RRIRPRPPRLPRPRPRPLPFPRPGPR
1976


BACTENECIN 7
PIPRPLPFPRPGPRPIPRPLPFPRPGP



(bac7, cow
RPIPRPL



cathelicidin)





AP00200
P21564,
LKLKSIVSWAKKVL
1977


Mastoparan B




(MP-B, insect,




XXA)





AP00005
P21663, Andropin
VFIDILDKVENAIHNAAQVGIGFAK
1978


(insect, fly)
PFEKLINPK




AP00008
P22226, Cyclic
RLCRIVVIRVCR
1979


dodecapeptide




(cow cathelicidin)





AP01205
P23826, Lactocin S
STPVLASVAVSMELLPTASVLYSD
1980


(XXD3, bacteria)
VAGCFKYSAKHHC




AP00239
P24335, XPF (the
GWASKIGQTLGKIAKVGLKELIQP
1981


xenopsin precursor
K



fragment, African




clawed frog)





AP00235
P25068, Bovine
NPVSCVRNKGICVPIRCPGSMKQIG
1982


tracheal
TCVGRAVKCCRKK



antimicrobial




peptide (TAP, cow)





AP00418
P25230, CAP18
GLRKRLRKFRNKIKEKLKKIGQKIQ
1983


(rabbit cathelicidin,
GFVPKLAPRTDY



BBL)





AP00203
P25403, Mj-AMP1
QCIGNGGRCNENVGPPYCCSGFCL
1984


(Mj AMP1, plant
RQPGQGYGYCKNR



defensin)





AP00202
P25404, Mj-AMP2
CIGNGGRCNENVGPPYCCSGFCLR
1985


(MjAMP2, plant
QPNQGYGVCRNR



defensin)





AP00138
P28310, Cryptdi n-3
LRDLVCYCRKRGCKRRERMNGTC
1986


(Crp3, animal
RKGHLMYTLCCR



defensin, alpha,




mouse)





AP00184
P28794, MBP-1
RSGRGECRRQCLRRHEGQPWETQ
1987


(plant)
ECMRRCRRRG




AP00050
P29002, Bombinin-
GIGASILSAGKSALKGLAKGLAEHF
1988


like peptide 1
AN



(BLP-1, toad)





AP00051
P29003, Bombinin-
GIGSAILSAGKSALKGLAKGLAEHF
1989


like peptide 2
AN



(BLP-2, toad)





AP00052
P29004, Bombinin-
GIGAAILSAGKSALKGLAKGLAEH
1990


like peptide 3
F



(BLP-3, XXA,




toad)





AP00053
P29005, Bombinin-
GIGAAILSAGKSIIKGLANGLAEHF
1991


like peptide 4




(BLP-4, toad)





AP00634
P29430, Pediocin
KYYGNGVTCGKHSCSVDWGKATT
1992


PA-1/ AcH
CIINNGAMAWATGGHQGNHKC



(PedPA1, class IIA




bacteriocin, bacteria)





AP00204
P29559, Nisin Z
ITSISLCTPGCKTGALMGCNMKTA
1993


(lantibiotic, class I
TCNCSIHVSK



bacteriocin,




bacteria)





AP00130
P29561, Cecropin
GWLKKLGKRIERIGQHTRDATIQG
1994


C (insect, fly)
LGIAQQAANVAATAR




AP00001
P31107,
GLWSKIKEVGKEAAKAAAKAAGK
1995


ADENOREGULIN
AALGAVSEAV



(Dermaseptin B2,




Dermaseptin-B2,




DRS-B2, DRS B2,




frog)





AP00228
P31529, Sapecin B
LTCEIDRSLCLLHCRLKGYLRAYCS
1996


(insect, flesh fly)
QQKVCRCVQ




AP00229
P31530, Sapecin C
ATCDLLSGIGVQHSACALHCVFRG
1997


(insect, flesh fly)
NRGGYCTGKGICVCRN




AP00218
P32195, Protegrin
RGGRLCYCRRRFCICV
1998


2 (PG-2, pig




cathelicidin)





AP00219
P32196, Protegrin
RGGGLCYCRRRFCVCVGR
1999


3 (PG-3, pig




cathelicidin)





AP00073
P32412, Brevinin-
FLPLLAGLAANFLPKIFCKITRKC
2000


1E (frog)





AP00080
P32414,
GIFSKLGRKKIKNLLISGLKNVGKE
2001


Esculentin-1 (frog)
VGMDVVRTGIDIAGCKIKGEC




AP00074
P32423, Brevinin-1
FLPVLAGIAAKVVPALFCKITKKC
2002


(frog)





AP00075
P32424, Brevinin-2
GLLDSLKGFAATAGKGVLQSLLST
2003


(frog)
ASCKLAKTC




AP00175
P34084, Macaque
DSHEERHHGRHGHHKYGRKFHEK
2004


histatin (M-Histatin
HHSHRGYRSNYLYDN



1, primate,




monkey)





AP00006
P35581, Apidaecin
GNNRPVYIPQPRPPHPRI
2005


IA (insect,




honeybee)





AP00007
P35581, Apidaecin
GNNRPVYIPQPRPPHPRL
2006


IB (insect,




honeybee)





AP00414
P36190,
SIGSALKKALPVAKKIGKIALPIAK
2007


Ceratotoxin A
AALP



(insect, fly)





AP00415
P36191,
SIGSAFKKALPVAKKIGKAALPIAK
2008


Ceratotoxin B
AALP



(insect, fly)





AP00172
P36193, Drosocin
GKPRPYSPRPTSHPRPIRV
2009


(insect)





AP00170
P37362, Pyrrhocoricin
VDKGSYLPRPTPPRPIYNRN
2010


(insect)





AP00635
P38577,
KYYGNGVHCTKSGCSVNWGEAAS
2011


Mesentericin Y105
AGIHRLANGGNGFW



(MesY105, class




IIA bacteriocin,




bacteria)





AP00636
P38579,
AISYGNGVYCNKEKCWVNKAENK
2012


Carnobacteriocin
QAITGIVIGGWASSLAGMGH



BM1 (CnbBM1,




PiscV1b, class IIA




bacteriocin,




bacteria)





AP00209
P39080, Peptide
GVLSNVIGYLKKLGTGALNAVLK
2013


PGQ (frog)
Q




AP00513
P39084, Ranalexin
FLGGLIKIVPAMICAVTKKC
2014


(frog)





AP00071
P40835, Brevinin-
FLPAIFRMAAKVVPTIICSITKKC
2015


1EA (frog)





AP00072
P40836, Brevinin-
VIPFVASVAAEMQHVYCAASRKC
2016


1EB (frog)





AP00076
P40837, Brevinin-
GILDTLKNLAISAAKGAAQGLVNK
2017


2EA (frog)
ASCKLSGQC




AP00077
P40838, Brevinin-
GILDTLKNLAKTAGKGALQGLVK
2018


2EB (frog)
MASCKLSGQC




AP00078
P40839, Brevinin-
GILLDKLKNFAKTAGKGVLQSLLN
2019


2EC (frog)
TASCKLSGQC




AP00079
P40840, Brevinin-
GILDSLKNLAKNAGQILLNKASCK
2020


2ED (frog)
LSGQC




AP00081
P40843,
GIFSKLAGKKIKNLLISGLKNVGKE
2021


Esculentin-1A
VGMDVVRTGIDIAGCKIKGEC



(frog)





AP00082
P40844,
GIFSKLAGKKLKNLLISGLKNVGK
2022


Esculentin-1B
EVGMDVVRTGIDIAGCKIKGEC



(frog)





AP00083
P40845,
GILSLVKGVAKLAGKGLAKEGGKF
2023


Esculentin-2A
GLELIACKIAKQC



(frog)





AP00084
P40846,
GIFSLVKGAAKLAGKGLAKEGGKF
2024


Esculentin-2B
GLELIACKIAKQC



(ES2B RANES,




frog)





AP00299
P46156, Chicken
GRKSDCFRKSGFCAFLKCPSLTLIS
2025


gallinacin 1 (Gal 1,
GKCSRFYLCCKRIW



avian beta-




defensin, bird)





AP00300
P46157, Gallinacin
GRKSDCFRKNGFCAFLKCPYLTLIS
2026


1 alpha (avian beta-
GKCSRFHLCCKRIW



defensin, Bird),





AP00298
P46158, Chicken
LFCKGGSCHFGGCPSHLIKVGSCFG
2027


gallinacin 2 (Gal 2,
FRSCCKWPWNA



avian beta-




defensin, bird)





AP00037
P46160, Beta-
VRNHVTCRINRGFCVPIRCPGRTRQ
2028


defensin 2 (cow)
IGTCFGPRIKCCRSW




AP00038
P46161, Beta-
QGVRNHVTCRINRGFCVPIRCPGR
2029


defensin 3 (cow)
TRQIGTCFGPRIKCCRSW




AP00039
P46162, Beta-
QRVRNPQSCRWNMGVCIPFLCRV
2030


defensin 4 (cow)
GMRQIGTCFGPRVPCCRR




AP00040
P46163, Beta-
QVVRNPQSCRWNMGVCIPISCPGN
2031


defensin 5 (cow)
MRQIGTCFGPRVPCCRRW




AP00041
P46164, Beta-
QGVRNHVTCRIYGGFCVPIRCPGR
2032


defensin 6 (cow)
TRQIGTCFGRPVKCCRRW




AP00042
P46165, Beta-
QGVRNFVTCRINRGFCVPIRCPGHR
2033


defensin 7 (cow)
RQIGTCLGPRIKCCR




AP00043
P46166, Beta-
VRNFVTCRINRGFCVPIRCPGHRRQ
2034


defensin 8 (cow)
IGTCLGPQIKCCR




AP00044
P46167, Beta-
QGVRNFVTCRINRGFCVPIRCPGHR
2035


defensin 9 (cow)
RQIGTCLAPQIKCCR




AP00045
P46168, Beta-
QGVRSYLSCWGNRGICLLNRCPGR
2036


defensin 10 (cow)
MRQIGTCLAPRVKCCR




AP00046
P46169, Beta-
GPLSCRRNGGVCIPIRCPGPMRQIG
2037


defensin 11 (cow)
TCFGRPVKCCRSW




AP00048
P46171, Bovine
SGISGPLSCGRNGGVCIPIRCPVPM
2038


beta-defensin 13
RQIGTCFGRPVKCCRSW



(cow)





AP00350
P48821, Enbocin
PWNIFKEIERAVARTRDAVISAGPA
2039


(insect, moth)
VRTVAAATSVAS




AP00173
P49112, GNCP-2
RCICTTRTCRFPYRRLGTCLFQNRV
2040


(Guinea pig
YTFCC



neutrophil cationic




peptide 2)





AP00369
P49930, PMAP-23
RIIDLLWRVRRPQKPKFVTVWVR
2041


(PMAP23, pig




cathelicidin)





AP00370
P49931, PMAP-36
VGRFRRLRKKTRKRLKKIGKVLK
2042


(PMAP36, pig
WIPPIVGSIPLGCG



cathelicidin)





AP00371
P49932, PMAP-37
GLLSRLRDFLSDRGRRLGEKIERIG
2043


(PMAP37, pig
QKIKDLSEFFQS



cathelicidin)





AP00220
P49933, Protegrin
RGGRLCYCRGWICFCVGR
2044


4 (PG-4, pig




cathelicidin)





AP00221
P49934, Protegrin
RGGRLCYCRPRFCVCVGR
2045


5 (PG-5, pig




cathelicidin)





AP00346
P50720, Hyphancin
RWKIFKKIERVGQNVRDGIIKAGP
2046


MD (Fall
AIQVLGTAKAL



webworm, insect)





AP00347
P50721, Hyphancin
RWKFFKKIERVGQNVRDGLIKAGP
2047


IIIE (Fall
AIQVLGAAKAL



webworm, insect)





AP 00348
P50722, Hyphancin
RWKVFKKIEKVGRNIRDGVIKAGP
2048


IIIF (Fall
AIAVVGQAKAL



webworm, insect)





AP00349
P50723, Hyphancin
RWKVFKKIEKVGRHIRDGVIKAGP
2049


IIIG (Fall
AITVVGQATAL



webworm, insect)





AP00281
P51473, mCRAMP
GLLRKGGEKIGEKLKKIGQKIKNFF
2050


(mouse
QKLVPQPEQ



cathelicidin;




derivatives:




CRAMP 18)





AP00366
P54228, BMAP-27
GRFKRFRKKFKKLFKKLSPVIPLLH
2051


(BMAP27, cow
LG



cathelicidin, ZZHs,




derivatives BMAP-




18 and BMAP-15)





AP00367
P54229, BMAP-28
GGLRSLGRKILRAWKKYGPIIVPIIR
2052


(BMAP28, cow
IG



cathelicidin)





AP00450
P54230, Cyclic
RICRIIFLRVCR
2053


dodecapeptide




(sheep cathelicidin)





AP00359
P54684, Lebocin
DLRFLYPRGKLPVPTPPPFNPKPIYI
2054


1/2 (insect, silk
DMGNRY



moth)





AP00360
P55796, Lebocin 3
DLRFLYPRGKLPVPTLPPFNPKPIYI
2055


(insect, silk moth)
DMGNRY




AP00307
P55897, Buforin I
AGRGKQGGKVRAKAKTRSSRAGL
2056


(toad)
QFPVGRVHRLLRKGNY




AP00308
P55897, Buforin II
TRSSRAGLQFPVGRVHRLLRK
2057


(toad)





AP00240
P56226, Caerin 1.1
GLLSVLGSVAKHVLPHVVPVIAEH
2058


(frog, ZZHa)
L




AP00241
P56227, Caerin 1.2
GLLGVLGSVAKHVLPHVVPVIAEH
2059


(frog)
L




AP00242
P56228, Caerin 1.3
GLLSVLGSVAQHVLPHVVPVIAEH
2060


(frog)
L




AP00243
P56229, Caerin 1.4
GLLSSLSSVAKHVLPHVVPVIAEHL
2061


(frog)





AP00244
P56230, Caerin 1.5
GLLSVLGSVVKHVIPHVVPVIAEHL
2062


(frog)





AP00245
P56231, Caerin 1.6
GLFSVLGAVAKHVLPHVVPVIAEK
2063


(frog)





AP00246
P56232, Caerin 1.7
GLFKVLGSVAKHLLPHVAPVIAEK
2064


(frog)





AP00249
P56233, Caerin 2.1
GLVSSIGRALGGLLADVVKSKGQP
2065


(frog)
A




AP00250
P56234, Caerin 2.2
GLVSSIGRALGGLLADVVKSKEQP
2066


(frog)
A




AP00251
P56236, Caerin 2.4
GLVSSIGKALGGLLADVVKTKEQP
2067


(frog)
A




AP00252
P56236, Caerin 2.5
GLVSSIGRALGGLLADVVKSKEQP
2068


(frog)
A




AP00253
P56238, Caerin 3.1
GLWQKIKDKASELVSGIVEGVK
2069


(frog)





AP00254
P56238, Caerin 3.2
GLWEKIKEKASELVSGIVEGVK
2070


(frog)





AP00255
P56240, Caerin 3.3
GLWEKIKEKANELVSGIVEGVK
2071


(frog)





AP00256
P56241, Caerin 3.4
GLWEKIREKANELVSGIVEGVK
2072


(frog)





AP00257
P56242, Caerin 4.1
GLWQKIKSAAGDLASGIVEGIKS
2073


(frog)





AP00258
P56243, Caerin 4.2
GLWQKIKSAAGDLASGIVEAIKS
2074


(frog)





AP00259
P56244, Caerin 4.3
GLWQKIKNAAGDLASGIVEGIKS
2075


(frog)





AP00434
P56249, Frenatin 3
GLMSVLGHAVGNVLGGLFKS
2076


(frog)





AP00272
P56386, Murine
DQYKCLQHGGFCLRSSCPSNTKLQ
2077


beta-defensin 1
GTCKPDKPNCCKS



(mBD-1, mouse)





AP00368
P56425, BMAP-34
GLFRRLRDSIRRGQQKILEKARRIG
2078


(BMAP34, cow
ERIKDIFRG



cathelicidin)





AP00273
P56685, Buthinin
SIVPIRCRSNRDCRRFCGFRGGRCT
2079


(Sahara scorpion)
YARQCLCGY




AP00282
P56872,
SIPCGESCVFIPCTVTALLGCSCKSK
2080


Cyclopsychotride
VCYKN



A (CPT, plant




cyclotides, XXC)





AP00094
P56917, Temporin
FLPLIGRVLSGIL
2081


A (XXA, frog)





AP00096
P56918, Temporin
LLPILGNLLNGLL
2082


C (XXA, frog)





AP00097
P56920, Temporin
VLPIIGNLLNSLL
2083


E (XXA,frog)





AP00098
P56921, Temporin
FLPLIGKVLSGIL
2084


F (XXA,frog)





AP00100
P56923, Temporin
LLPNLLKSLL
2085


K (XXA,frog)





AP00295
P56928, eNAP-2
EVERKHPLGGSRPGRCPTVPPGTF
2086


(horse)
GHCACLCTGDASEPKGQKCCSN




AP00101
P57104, Temporin
FVQWFSKFLGRIL
2087


L (XXA,frog)





AP00095
P79874, Temporin
LLPIVGNLLKSLL
2088


B (XXA, frog)





AP00099
P79875, Temporin
FFPVIGRILNGIL
2089


G (XXA,frog)





AP00413
P80032,
SLQGGAPNFPQPSQQNGGWQVSP
2090


Coleoptericin
DLGRDDKGNTRGQIEIQNKGKDH



(insect)
DFNAGWGKVIRGPNKAKPTWHVG




GTYRR




AP00396
P80054, PR-39
RRRPRPPYLPRPRPPPFFPPRLPPRIP
2091


(PR39, pig
PGFPPRFPPRFP



cathelicidin)





AP00182
P80154, Insect
GFGCPLDQMQCHRHCQTITGRSGG
2092


defensin
YCSGPLKLTCTCYR




AP00444
P80223,
GICACRRRFCLNFEQFSGYCRVNG
2093


Corticostatin VI
ARYVRCCSRR



(CS-VI) (animal




defensin, rabbit)





AP00208
P80230, Peptide
RADTQTYQPYNKDWIKEKIYVLLR
2094


3910 (pig)
RQAQQAGK




AP00157
P80277,
ALWKTMLKKLGTMALHAGKAAL
2095


Dermaseptin-S1
GAAADTISQGTQ



(Dermaseptin S1,




DRS S1, DRS-S1,




frog)





AP00158
P80278,
ALWFTMLKKLGTMALHAGKAAL
2096


Dermaseptin-S2
GAAANTISQGTQ



(Dermaseptin S2,




DRS S2, DRS-S2,




frog)





AP00159
P80279,
ALWKNMLKGIGKLAGKAALGAV
2097


Dermaseptin-S3
KKLVGAES



(Dermaseptin S3,




DRS S3, DRS-S3,




frog)





AP00160
P80280,
ALWMTLLKKVLKAAAKALNAVL
2098


Dermaseptin-S4
VGANA



(Dermaseptin S4,




DRS S4, DRS-S4,




frog)





AP00161
P80281,
GLWSKIKTAGKSVAKAAAKAAVK
2099


Dermaseptin-S5
AVTNAV



(Dermaseptin S5,




DRS S5, DRS-S5,




frog)





AP00293
P80282,
AMWKDVLKKIGTVALHAGKAAL
2100


Dermaseptin-B1
GAVADTISQ



(DRS-B1, DRS B1,




frog)





AP00264
P80389, Chicken
GRKSDCFRKSGFCAFLKCPSLTLIS
2101


Heterophil Peptide
GKCSRFYLCCKRIR



1 (CHP1, bird,




animal)





AP00265
P80390, Chicken
GRKSDCFRKNGFCAFLKCPYLTLIS
2102


Heterophil Peptide
GLCSFHLC



2 (CHP2, bird,




animal)





AP00266
P80391, Turkey
GKREKCLRRNGFCAFLKCPTLSVIS
2103


Heterophil Peptide
GTCSRFQVCC



1 (THP1, turkey)





AP00267
P80392, Turkey
LFCKRGTCHFGRCPSHLIKVGSCFG
2104


Heterophil Peptide
FRSCCKWPWDA



2 (THP2, bird,




anaimal)





AP00269
P80393, Turkey
LSCKRGTCHFGRCPSHLIKGSCSGG
2105


Heterophil Peptide




3 (THP3, bird,




animal)





AP00085
P80395, Gaegurin-
SLFSLIKAGAKFLGKNLLKQGACY
2106


1 (Gaegurin 1,
AACKASKQC



frog)





AP00086
P80396, Gaegurin-
GIMSIVKDVAKNAAKEAAKGALST
2107


2 (Gaegurin 2,
LSCKLAKTC



frog)





AP00087
P80397, Gaegurin-
GIMSIVKDVAKTAAKEAAKGALST
2108


3 (Gaegurin 3,
LSCKLAKTC



frog)





AP00089
P80399, Gaegurin-
FLGALFKVASKVLPSVFCAITKKC
2109


5 (Gaegurin 5,




frog)





AP00090
P80400, Gaegurin-
FLPLLAGLAANFLPTIICKISYKC
2110


6 (Gaegurin 6,




frog)





AP00362
P80408,
VDKPDYRPRPRPPNM
2111


Metalnikowin I




(insect)





AP00363
P80409,
VDKPDYRPRPWPRPN
2112


Metalnikowin IIA




(insect)





AP00364
P80410,
VDKPDYRPRPWPRNMI
2113


Metalnikowin IIB




(insect)





AP00365
P80411,
VDKPDYRPRPWPRPNM
2114


Metalnikowin III




(insect)





AP00632
P80569, Piscicolin
KYYGNGVSCNKNGCTVDWSKAIG
2115


126/Piscicocin
IIGNNAAANLTTGGAAGWNKG



Via (PiscV1a,




Pisc126, class IIA




bacteriocin,




bacteria)





AP01003
P80666, Mutacin
FKSWSFCTPGCAKTGSFNSYCC
2116


B-Ny266 (bacteria)





AP00276
P80710, Clavanin
VFQFLGKIIHHVGNFVHGFSHVF
2117


A (urochordates,




sea squirts, and sea




pork, tunicate)





AP00277
P80711, Clavanin
VFQFLGRIIHHVGNFVHGFSHVF
2118


B (Sea squirt,




tunicate)





AP00278
P80712, Clavanin
VFHLLGKIIHHVGNFVYGFSHVF
2119


C (Sea squirt,




tunicate)





AP00279
P80713, Clavanin
AFKLLGRIIHHVGNFVYGFSHVF
2120


D (Sea squirt,




tunicate)





AP00280
P80713, Clavanin
LFKLLGKIIHHVGNFVHGFSHVF
2121


D (Sea squirt,




tunicate)





AP00294
P80930, eNAP-1
DVQCGEGHFCHDQTCCRASQGGA
2122


(horse)
CCPYSQGVCCADQRHCCPVGF




AP00400
P80952, Skin
YPPKPESPGEDASPEEMNKYLTAL
2123


peptide tyrosine-
RHYINLVTRQRY



tyrosine (skin-




PYY, SPYY, frog)





AP00091
P80954, Rugosin A
GLLNTFKDWAISIAKGAGKGVLTT
2124


(frog)
LSCKLDKSC




AP00092
P80955, Rugosin B
SLFSLIKAGAKFLGKNLLKQGAQY
2125


(frog)
AACKVSKEC




AP00093
P80956, Rugosin C
GILDSFKQFAKGVGKDLIKGAAQG
2126


(frog)
VLSTMSCKLAKTC




AP00392
P81056, Penaeidin-
YRGGYTGPIPRPPPIGRPPLRLVVC
2127


1 (shrimp,
ACYRLSVSDARNCCIKFGSCCHLV



Crustacea)
K




AP00393
P81057, Penaeidin-
YRGGYTGPIPRPPPIGRPPFRPVCN
2128


2a (shrimp,
ACYRLSVSDARNCCIKFGSCCHLV



Crustacea)
K




AP00394
P81058, Penaeidin-
QVYKGGYTRPIPRPPPFVRPLPGGP
2129


3a (shrimp,
IGPYNGCPVSCRGISFSQARSCCSR



Crustacea)
LGRCCHVGKGYS




AP00247
P81251, Caerin 1.8
GLFKVLGSVAKHLLPHVVPVIAEK
2130


(frog)





AP00248
P81252, Caerin 1.9
GLFGVLGSIAKHVLPHVVPVIAEK
2131


(frog, ZZHa)





AP00126
P81417, Cecropin
GGLKKLGKKLEGVGKRVFKASEK
2132


A (insect,
ALPVAVGIKALG



mosquito)





AP00169
P81437, Formaecin
GRPNPVNTKPTPYPRL
2133


2 (insect, ants)





AP00168
P81438, Formaecin
GRPNPVNNKPTPHPRL
2134


1 (insect, ants)





AP00296
P81456, Fabatin -1
LLGRCKVKSNRFHGPCLTDTHCST
2135


(plant defensin)
VCRGEGYKGGDCHGLRRRCMCLC




AP00297
P81457, Fabatin -2
LLGRCKVKSNRFNGPCLTDTHCST
2136


(plant defensin)
VCRGEGYKGGDCHGLRRRCMCLC




AP01215
P81463, European
FVPYNPPRPYQSKPFPSFPGHGPFN
2137


bumblebee abaecin
PKIQWPYPLPNPGH



(insect)





AP01214
P81464, Apidaecin
GNRPVYIPPPRPPHPRL
2138


(insect)





AP00440
P81465, defensin
VTCFCRRRGCASRERHIGYCRFGN
2139


HANP-1 (hamster)
TIYRLCCRR




AP00441
P81466, defensin
CFCKRPVCDSGETQIGYCRLGNTF
2140


HANP-2 (hamster)
YRLCCRQ




AP00442
P81467, defensin
VTCFCRRRGCASRERLIGYCRFGN
2141


HANP-3 (hamster)
TIYGLCCRR




AP00439
P81468, defensin
VTCFCKRPVCDSGETQIGYCRLGN
2142


HANP-4 (hamster)
TFYRLCCRQ




AP00328
P81469, Styelin A
GFGKAFHSVSNFAKKHKTA
2143


(Sea squirt,




tunicate, XXA)





AP00329
P81470, Styelin B
GFGPAFHSVSNFAKKHKTA
2144


(Sea squirt,




tunicate, XXA)





AP00492
P81474, Misgurin
RQRVEELSKFSKKGAAARRRK
2145


(fish)





AP00165
P81485,
ALWKNMLKGIGKLAGQAALGAV
2146


Dermaseptin-B3
KTLVGAE



(Dermaseptin B3,




DRS-B3, DRS B3,




frog)





AP00163
P81486,
ALWKDILKNVGKAAGKAVLNTVT
2147


Dermaseptin-B4
DMVNQ



(Dermaseptin B4,




DRS-B4, DRS B4,




DRS-TR1, IRP,




frog)





AP00162
P81487,
GLWNKIKEAASKAAGKAALGFVN
2148


Dermaseptin-B5
EMV



(Dermaseptin B5,




DRS-B5, DRS B5,




frog)





AP00164
P81488,
ALWKTIIKGAGKMIGSLAKNLLGS
2149


Dermaseptin-B9
QAQPES



(Dermaseptin B9,




DRS-B9, DRS




DRG3, frog)





AP00167
P81565, Phylloxin
GWMSKIASGIGTFLSGMQQ
2150


(phylloxin-B1,




PLX-B1, XXA,




frog)





AP00291
P81568, Defensin
NIFFSSKKCKTVSKTFRGPCVRNAN
2151


D5 (So-D5) (plant




defensin)





AP00290
P81569, Defensin
NIFFSSKKCKTVSKTFRGPCVRNA
2152


D4 (So-D4) (plant




defensin)





AP00289
P81570, Defensin
GIFSSRKCKTVSKTFRGICTRNANC
2153


D3 (So-D3) (plant




defensin)





AP00288
P81572, Defensin
TCESPSHKFKGPCATNRNCES
2154


D1 (So-D1) (plant




defensin)





AP00292
P81573, Defensin
GIFSSRKCKTPSKTFKGYCTRDSNC
2155


D7 (So-D7) (plant
DTSCRYEGYPAGD



defensin)





AP00270
P81591, Pn-AMP
QQCGRQASGRLCGNRLCCSQWGY
2156


(PnAMP, plant
CGSTASYCGAGCQSQCRS



defensin)





AP00412
P81592,
SLQPGAPNVNNKDQPWQVSPHISR
2157


Acaloleptin A1
DDSGNTRTDINVQRHGENNDFEAG



(insect)
WSKVVRGPNKAKPTWHIGGTHRW




AP00433
P81605, human
SSLLEKGLDGAKKAVGGLGKLGK
2158


Dermcidin (DCD-
DAVEDLESVGKGAVHDVKDVLDS



1)
V




AP00332
P81612, Mytilin A
GCASRCKAKCAGRRCKGWASASF
2159


(Blue mussel)
RGRCYCKCFRC




AP00333
P81613, Mytilin B
SCASRCKGHCRARRCGYYVSVLY
2160


(Blue mussel)
RGRCYCKCLRC




AP00334
P81613,
FFHHIFRGIVHVGKTIHKLVTG
2161


Moronecidin (fish)





AP00351
P81835, Citropin
GLFDVIKKVASVIGGL
2162


1.1 (amphibian,




frog)





AP00352
P81840, Citropin
GLFDIIKKVASVVGGL
2163


1.2 (amphibian,




frog)





AP00353
P81846, Citropin
GLFDIIKKVASVIGGL
2164


1.3 (amphibian,




frog)





AP00338
P81903, Hi stone
PDPAKTAPKKGSKKAVTKA
2165


H2B-1(HLP-1)




(fish)





AP00271
P82018, ChB ac5
RFRPPIRRPPIRPPFNPPFRPPVRPPF
2166


(Goat cathelicidin)
RPPFRPPFRPPIGPFP




AP00316
P82027, Uperin 2.1
GIVDFAKKVVGGIRNALGI
2167


(amphibian, toad)





AP00317
P82028, Uperin 2.2
GFVDLAKKVVGGIRNALGI
2168


(amphibian, toad)





AP00318
P82029, Uperin 2.3
GFFDLAKKVVGGIRNALGI
2169


(amphibian, toad)





AP00319
P82030, Uperin 2.4
GILDFAKTVVGGIRNALGI
2170


(amphibian, toad)





AP00320
P82031, Uperin 2.5
GIVDFAKGVLGKIKNVLGI
2171


(amphibian, toad)





AP00323
P82032, Uperin 3.1
GVLDAFRKIATVVKNVV
2172


(amphibian, toad)





AP00326
P82035, Uperin 4.1
GVGSFIHKVVSAIKNVA
2173


(amphibian, toad)





AP00321
P82039, Uperin 2.7
GIIDIAKKLVGGIRNVLGI
2174


(amphibian, toad)





AP00322
P82040, Uperin 2.8
GILDVAKTLVGKLRNVLGI
2175


(amphibian, toad)





AP00324
P82042, Uperin 3.5
GVGDLIRKAVSVIKNIV
2176


(amphibian, toad)





AP00325
P82042, Uperin 3.6
GVIDAAKKVVNVLKNLP
2177


(amphibian, toad)





AP00327
P82050, Uperin 7.1
GWFDVVKHIASAV
2178


(amphibian, frog)





AP00260
P82066, Maculatin
GLFVGVLAKVAAHVVPAIAEHF
2179


1.1 (XXA, frog,




ZZHa)





AP00261
P82067, Maculatin
GLFVGLAKVAAHNNPAIAEHFQA
2180


1.2 (XXA, frog)





AP00262
P82068, Maculatin
GFVDFLKKVAGTIANVVT
2181


2.1 (frog)





AP00263
P82069, Maculatin
GLLQTIKEKLESLESLAKGIVSGIQ
2182


3.1 (frog)
A




AP00345
P82104, Caerin
GLLSVLGSVAKHVLPHVVPVIAEK
2183


1.10 (frog)
L




AP00456
P82232, Brevinin-
VNPIILGVLPKFVCLITKKC
2184


1T (frog)





AP00459
P82233, Brevinin-
FITLLLRKFICSITKKC
2185


1TA (frog)





AP00457
P82234, Brevinin-
GLWETIKNFGKKFTLNILHKLKCKI
2186


2TC (frog)
GGGC




AP00458
P82235, Brevinin-
GLWETIKNFGKKFTLNILHNLKCKI
2187


2TD (frog)
GGGC




AP00397
P82238,
SGFVLKGYTKTSQ
2188


Salmocidin 2A




(fish, trout)





AP00398
P82239,
AGFVLKGYTKTSQ
2189


Salmocidin 2B




(fish, trout)





AP00055
P82282, Bombinin
IIGPVLGMVGSALGGLLKKI
2190


H1 (frog)





AP00056
P82284, Bombinin
LIGPVLGLVGSALGGLLKKI
2191


H4 (frog, XXA,




XXD)





AP00057
P82285, Bombinin
IIGPVLGLVGSALGGLLKKI
2192


H5 (frog, XXD)





AP00419
P82286, Bombinin-
GIGASILSAGKSALKGFAKGLAEHF
2193


like peptides 2
AN



(amphibian, toad)





AP00137
P82293, Cryptdin-1
LRDLVCYCRTRGCKRRERMNGTC
2194


(Crp1, animal
RKGHLMYTLCCR



defensin, alpha,




mouse)





AP00443
P82317, defensin
ACYCRIPACLAGERRYGTCFYMGR
2195


RMAD-2 (monkey)
VWAFCC




AP00012
P82386, Aurein 1.1
GLFDIIKKIAESI
2196


(amphibian,frog)





AP00014
P82388, Aurein 2.1
GLLDIVKKVVGAFGSL
2197


(amphibian,frog)





AP00015
P82389, Aurein 2.2
GLFDIVKKVVGALGSL
2198


(amphibian,frog)





AP00016
P82390, Aurein 2.3
GLFDIVKKVVGAIGSL
2199


(XXA,




amphibian,frog)





AP00017
P82391, Aurein 2.4
GLFDIVKKVVGTIAGL
2200


(XXA,




amphibian,frog)





AP00018
P82392, Aurein 2.5
GLFDIVKKVVGAFGSL
2201


(XXA,




amphibian,frog)





AP00019
P82393, Aurein 2.6
GLFDIAKKVIGVIGSL
2202


(XXA,




amphibian,frog)





AP00020
P82394, Aurein 3.1
GLFDIVKKIAGHIAGSI
2203


(XXA,




amphibian,frog)





AP00021
P82395, Aurein 3.2
GLFDIVKKIAGHIASSI
2204


(XXA,




amphibian,frog)





AP00022
P82396, Aurein 3.3
GLFDIVKKIAGHIVSSI
2205


(XXA,




amphibian,frog)





AP00376
P82414, Ponericin
GWKDWAKKAGGWLKKKGPGMA
2206


G1 (ants)
KAALKAAMQ




AP00377
P82415, Ponericin
GWKDWLKKGKEWLKAKGPGIVK
2207


G2 (ants)
AALQAATQ




AP00378
P82416, Ponericin
GWKDWLNKGKEWLKKKGPGIMK
2208


G3 (ants)
AALKAATQ




AP00379
P82417, Ponericin
DFKDWMKTAGEWLKKKGPGILKA
2209


G4 (ants)
AMAAAT




AP00380
P82418, Ponericin
GLKDWVKIAGGWLKKKGPGILKA
2210


G5 (ants)
AMAAATQ




AP00381
P82419, Ponericin
GLVDVLGKVGGLIKKLLP
2211


G6 (ants)





AP00382
P82420, Ponericin
GLVDVLGKVGGLIKKLLPG
2212


G7 (ants)





AP00383
P82421, Ponericin
LLKELWTKMKGAGKAVLGKIKGL
2213


L1 (ants)
L




AP00384
P82422, Ponericin
LLKELWTKIKGAGKAVLGKIKGLL
2214


L2 (ants)





AP00386
P82423, Ponericin
WLGSALKIGAKLLPSVVGLFKKKK
2215


W1 (ants)
Q




AP00387
P82424, Ponericin
WLGSALKIGAKLLPSVVGLFQKKK
2216


W2 (ants)
K




AP00388
P82425, Ponericin
GIWGTLAKIGIKAVPRVISMLKKK
2217


W3 (ants)
KQ




AP00389
P82426, Ponericin
GIWGTALKWGVKLLPKLVGMAQT
2218


W4 (ants)
KKQ




AP00390
P82427, Ponericin
FWGALIKGAAKLIPSVVGLFKKKQ
2219


W5 (ants)





AP00391
P82428, Ponericin
FIGTALGIASAIPAIVKLFK
2220


W6 (ants)





AP00303
P82651, Tigerinin-
FCTMIPIPRCY
2221


1 (frog)





AP00304
P82652, Tigerinin-
RVCFAIPLPICH
2222


2 (frog)





AP00305
P82653, Tigerinin-
RVCYAIPLPICY
2223


3 (frog)





AP00301
P82656, Hadrurin
GILDTIKSIASKVWNSKTVQDLKR
2224


(scorpion)
KGINWVANKLGVSPQAA




AP00113
P82740,
GLLSGLKKVGKHVAKNVAVSLMD
2225


RANATUERIN 1T
SLKCKISGDC



(frog)





AP00114
P82741,
SMLSVLKNLGKVGLGFVACKINK
2226


RANATUERIN 1
QC



(Ranatuerin-1,




frog)





AP00115
P82742,
GLFLDTLKGAAKDVAGKLEGLKC
2227


RANATUERIN 2
KITGCKLP



(Ranatuerin-2,




frog)





AP00116
P82780,
GFLDIINKLGKTFAGHMLDKIKCTI
2228


RANATUERIN 3
GTCPPSP



(Ranatuerin-3,




frog)





AP00117
P82819,
FLPFIARLAAKVFPSIICSVTKKC
2229


RANATUERIN 4




(Ranatuerin-4,




frog)





AP00405
P82821,
FISAIASMLGKFL
2230


RANATUERIN 6




(frog)





AP00406
P82822,
FLSAIASMLGKFL
2231


RANATUERI 7




(frog)





AP00407
P82823,
FISAIASFLGKFL
2232


RANATUERIN 8




(frog)





AP00408
P82824,
FLFPLITSFLSKVL
2233


RANATUERIN 9




(frog)





AP00461
P82825, Brevinin-
FLPMLAGLAASMVPKLVCLITKKC
2234


1LA (frog)





AP00462
P82826, Brevinin-
FLPMLAGLAASMVPKFVCLITKKC
2235


1LB (frog)





AP00118
P82828,
GILDSFKGVAKGVAKDLAGKLLD
2236


RANATUERIN
KLKCKITGC



2La (Ranatuerin-




2La, frog)





AP00119
P82829,
GILSSIKGVAKGVAKNVAAQLLDT
2237


RANATUERIN
LKCKITGC



2Lb (Ranatuerin-




2Lb, frog)





AP00109
P82830, Temporin-
VLPLISMALGKLL
2238


1La (Temporin




1La, frog)





AP00110
P82831, Temporin-
NFLGTLINLAKKIM
2239


1Lb (Temporin




1Lb, frog)





AP00111
P82832, Temporin-
FLPILINLIHKGLL
2240


1Lc (Temporin




1Lc, frog)





AP00463
P82833, Brevinin-
FLPFIAGMAAKFLPKIFCAISKKC
2241


1BA (frog)





AP00464
P82834, Brevinin-
FLPAIAGMAAKFLPKIFCAISKKC
2242


1BB (frog)





AP00465
P82835, Brevinin-
FLPFIAGVAAKFLPKIFCAISKKC
2243


1BC (frog)





AP00466
P82836, Brevinin-
FLPAIAGVAAKFLPKIFCAISKKC
2244


1BD (frog)





AP00467
P82837, Brevinin-
FLPAIVGAAAKFLPKIFCVISKKC
2245


1BE (frog)





AP00468
P82838, Brevinin-
FLPFIAGMAANFLPKIFCAISKKC
2246


1BF (frog)





AP00120
P82840,
GLLDTIKGVAKTVAASMLDKLKC
2247


RANATUERIN 2B
KISGC



(Ranatuerin-2B,




frog)





AP00469
P82841, Brevinin-
FLPIIAGVAAKVFPKIFCAISKKC
2248


1PA (frog)





AP00460
P82842, Brevinin-
FLPIIAGIAAKVFPKIFCAISKKC
2249


1PB (frog)





AP00470
P82843, Brevinin-
FLPIIASVAAKVFSKIFCAISKKC
2250


1PC (frog)





AP00471
P82844, Brevinin-
FLPIIASVAANVFSKIFCAISKKC
2251


1PD (frog)





AP00472
P82845, Brevinin-
FLPIIASVAAKVFPKIFCAISKKC
2252


1PE (frog)





AP00121
P82847,
GLMDTVKNVAKNLAGHMLDKLK
2253


RANATUERIN 2P
CKITGC



(Ranatuerin-2P,




frog)





AP00112
P82848, Temporin-
FLPIVGKLLSGLL
2254


1P (Temporin 1P,




frog)





AP00452
P82871, Brevinin-
FLPVVAGLAAKVLPSIICAVTKKC
2255


1SY (frog)





AP00122
P82875,
SMLSVLKNLGKVGLGLVACKINK
2256


Ranatuerin-1C
QC



(Ranatuerin 1C,




frog)





AP00514
P82876, Ranalexin-
FLGGLMKAFPALICAVTKKC
2257


1Ca (frog)





AP00515
P82877, Ranalexin-
FLGGLMKAFPAIICAVTKKC
2258


1Cb (frog)





AP00124
P82878,
GLFLDTLKGAAKDVAGKLLEGLK
2259


Ranatuerin-2Ca
CKIAGCKP



(Ranatuerin 2Ca,




frog)





AP00123
P82879,
GLFLDTLKGLAGKLLQGLKCIKAG
2260


Ranatuerin-2Cb
CKP



(Ranatuerin 2Cb,




frog)





AP00104
P82880, Temporin-
FLPFLAKILTGVL
2261


1Ca (Temporin




1Ca, frog)





AP00105
P82881, Temporin-
FLPLFASLIGKLL
2262


1Cb (Temporin




1Cb, frog)





AP00106
P82882, Temporin-
FLPFLASLLTKVL
2263


1Cc (Temporin




1Cc, frog)





AP00107
P82883, Temporin-
FLPFLASLLSKVL
2264


1Cd (Temporin




1Cd, frog)





AP00108
P82884, Temporin-
FLPFLATLLSKVL
2265


1Ce (Temporin




1Ce, frog)





AP00453
P82904, Brevinin-
FLPAIVGAAGQFLPKIFCAISKKC
2266


1SA (frog)





AP00454
P82905, Brevinin-
FLPAIVGAAGKFLPKIFCAISKKC
2267


1SB (frog)





AP00455
P82906, Brevinin-
FFPIVAGVAGQVLKKIYCTISKKC
2268


1SC (frog)





AP00996
P82907, Lichenin
ISLEICAIFHDN
2269


(bacteria)





AP00302
P82951, Hepcidin
GCRFCCNCCPNMSGCGVCCRF
2270


(fish)





AP00058
P83080, Maximin 1
GIGTKILGGVKTALKGALKELAST
2271


(toad)
YAN




AP00059
P83081, Maximin 2
GIGTKILGGVKTALKGALKELAST
2272


(toad)
YVN




AP00060
P83082, Maximin 3
GIGGKILSGLKTALKGAAKELAST
2273


(toad, ZZHa)
YLH




AP00061
P83083, Maximin 4
GIGGVLLSAGKAALKGLAKVLAE
2274


(toad)
KYAN




AP00062
P83084, Maximin 5
SIGAKILGGVKTFFKGALKELASTY
2275


(toad)
LQ




AP00063
P83085, Maximin 6
ILGPVISTIGGVLGGLLKNL
2276


(toad)





AP00064
P83086, Maximin 7
ILGPVLGLVGNALGGLIKNE
2277


(toad)





AP00065
P83087, Maximin 8
ILGPVLSLVGNALGGLLKNE
2278


(toad)





AP00355
P83171,
ANTAFVSSAHNTQKIPAGAPFNRN
2279


Ginkbilobin
LRAMLADLRQNAAFAG



(Chinese plant)





AP00475
P83188, Pseudin 1
GLNTLKKVFQGLHEAIKLINNHVQ
2280


(frog)





AP00476
P83189, Pseudin 2
GLNALKKVFQGIHEAIKLINNHVQ
2281


(frog)





AP00477
P83190, Pseudin 3
GINTLKKVIQGLHEVIKLVSNHE
2282


(frog)





AP00478
P83191, Pseudin 4
GINTLKKVIQGLHEVIKLVSNHA
2283


(frog)





AP00410
P83287,
SKGKKANKDVELARG
2284


Oncorhyncin III




(fish)





AP00357
P83305, Japonicin-
FFPIGVFCKIFKTC
2285


1 (amphibian, frog)





AP00358
P83306, Japonicin-
FGLPMLSILPKALCILLKRKC
2286


2 (amphibian, frog)





AP00385
P83312,
FKLGSFLKKAWKSKLAKKLRAKG
2287


Parabutoporin
KEMLKDYAKGLLEGGSEEVPGQ



(scorpion)





AP00374
P83313,
GKVWDWIKSTAKKLWNSEPVKEL
2288


Opistoporin 1
KNTALNAAKNLVAEKIGATPS



(scorpion)





AP00375
P83314,
GKVWDWIKSTAKKLWNSEPVKEL
2289


Opistoporin 2
KNTALNAAKNFVAEKIGATPS



(scorpion)





AP00336
P83327, Histone
AERVGAGAPVYL
2290


H2A (fish)





AP00335
P83338, Histone
PKRKSATKGDEPA
2291


H6-like protein




(fish)





AP00411
P83374,
KAVAAKKSPKKAKKPAT
2292


Oncorhyncin II




(fish)





AP00999
P83375, Serracin-P
DYHHGVRVL
2293


43 kDa subunit




(bacteria)





AP00284
P83376,
SHQDCYEALHKCMASHSKPFSCS
2294


Dolabellanin B2
MKFHMCLQQQ



(sea hare)





AP00998
P83378, Serracin-P
ALPKKLKYLNLFNDGFNYMGVV
2295


23 kDa subunit




(bacteriocin,




bacteria)





AP00129
P83403, Cecropin
GWLKKIGKKIERVGQNTRDATVK
2296


(insect, moth)
GLEVAQQAANVAATVR




AP00127
P83413, Cecropin
RWKVFKKIEKVGRNIRDGVIKAAP
2297


A (insect, moth)
AIEVLGQAKAL




AP00372
P83416, Virescein
GKIPIGAIKKAGKAIGKGLRAVNIA
2298


(insect)
STAHDVYTFFKPKKRH




AP00356
P83427, Heliocin
QRFIHPTYRPPPQPRRPVIMRA
2299


(insect)





AP00409
P83428, Locustin
ATTGCSCPQCIIFDPICASSYKNGRR
2300


(insect)
GFSSGCHMRCYNRCHGTDYFQISK




GSKCI




AP00339
P83545,
FFGWLIKGAIHAGKAIHGLIHRRRH
2301


Chrysophsin-1




(Red sea bream,




madai)





AP00340
P83546,
FFGWLIRGAIHAGKAIHGLIHRRRH
2302


Chrysophsin-2




(Red sea bream,




madai)





AP00341
P83547,
FIGLLISAGKAIHDLIRRRH
2303


Chrysophsin-3




(Red sea bream,




madai)





AP01004
P84763, Thuricin-S
DWTAWSALVAAACSVELL
2304


(bacteria)





AP00553
P84868, Sesquin
KTCENLADTY
2305


(plant, ZZHp)





AP00132
Q06589, Cecropin
GWLKKIGKKIERVGQHTRDATIQTI
2306


1 (insect, fly)
AVAQQAANVAATAR




AP00135
Q06590, Cecropin
GWLKKIGKKIERVGQHTRDATIQTI
2307


2 (insect fly)
GVAQQAANVAATLK




AP00416
Q17313,
SLGGVISGAKKVAKVAIPIGKAVLP
2308


Ceratotoxin C
VVAKLVG



(insect, fly)





AP00171
Q24395,
HRHQGPIFDTRPSPFNPNQPRPGPIY
2309


Metchnikowin




(insect)





AP00354
Q27023, Tenecin 1
VTCDILSVEAKGVKLNDAACAAH
2310


(insect)
CLFRGRSGGYCNGKRVCVCR




AP00401
Q28880, Lingual
GFTQGVRNSQSCRRNKGICVPIRCP
2311


antimicrobial
GSMRQIGTCLGAQVKCCRRK



peptide (LAP, beta




defensin, cow)





AP00224
Q62713, RatNP-3
CSCRTSSCRFGERLSGACRLNGRIY
2312


(rat)
RLCC




AP00225
Q62714, RatNP-4
ACYCRIGACVSGERLTGACGLNGR
2313


(rat)
IYRLCCR




AP00223
Q62715, RatNP-2
VTCYCRSTRCGFRERLSGACGYRG
2314


(rat)
RIYRLCCR




AP00222
Q62716, RatNP-1
VTCYCRRTRCGFRERLSGACGYRG
2315


(rat)
RIYRLCCR




AP00174
Q64365, GNCP-1
RRCICTTRTCRFPYRRLGTCIFQNR
2316


(Guinea pig
VYTFCC



neutrophil cationic




peptide 1)





AP00311
Q90W78, Galensin
CYSAAKYPGFQEFINRKYKSSRF
2317


(frog)





AP00395
Q95NT0,
HSSGYTRPLPKPSRPIFIIRPIGCDVC
2318


Penaeidin-4a
YGIPSSTARLCCFRYGDCCHR



(shrimp, Crustacea)





AP00423
Q962B0,
QGYKGPYTRPILRPYVRPVVSYNA
2319


Penaeidin-3n
CTLSCRGITTTQARSCSTRLGRCCH



(shrimp, Crustacea)
VAKGYS




AP00422
Q962B1,
QGCKGPYTRPILRPYVRPVVSYNA
2320


Penaeidin-3m
CTLSCRGITTTQARSCCTRLGRCCH



(shrimp, Crustacea)
VAKGYS




AP00421
Q963C3,
YSSGYTRPLPKPSRPIFIRPIGCDVC
2321


Penaeidin-4C
YGIPSSTARLCCFRYGDCCHR



(shrimp, Crustacea)





AP00210
Q99134, PGLa
GMASKAGAIAGKIAKVALKAL
2322


(African clawed




frog, XXA)





AP00054
Q9DET7,
GIGGALLSAGKSALKGLAKGLAEH
2323


Bombinin-like
FAN



peptide 7 (BLP-7,




toad)





AP00315
Q9PT75,
SLGSFLKGVGTTLASVGKVVSDQF
2324


Dermatoxin (Two-
GKLLQAGQ



colored leaf frog)





AP00133
Q9Y0Y0, Cecropin
GGLKKLGKKLEGVGKRVFKASEK
2325


B (insect,
ALPVLTGYKAIG



mosquito)





AP00004
Ref, Ct-AMP1
NLCERASLTWTGNCGNTGHCDTQ
2326


(CtAMP1, C.
CRNWESAKHGACHKRGNWKCFC



ternatea-
YFDC



antimicrobial




peptide 1, plant




defensin)





AP00027
Ref, hexapeptide
RRWQWR
2327


(synthetic)





AP00529
Ref, Lantibiotic
WKSESVCTPGCVTGVLQTCFLQTI
2328


Ericin S (bacteria)
TCNCHISK




AP00306
Ref, Tigerinin-4
RVCYAIPLPIC
2329


(frog)





AP00309
Ref, Human KS-27
KSKEKIGKEFKRIVQRIKDFLRNLV
2330


(KS27 from LL-37)
PR




AP00344
Ref, Apidaecin II
GNNRPIYIPQPRPPHPRL
2331


(honeybee, insect)





AP00424
Ref, XT 1 (frog)
GFLGPLLKLAAKGVAKVIPHLIPSR
2332



QQ




AP00425
Ref, XT 2 (frog)
GCWSTVLGGLKKFAKGGLEAIVNP
2333



K




AP00426
Ref, XT 4 (frog)
GVFLDALKKFAKGGMNAVLNPK
2334



AP00427
Ref, XT 7 (frog)
GLLGPLLKIAAKVGSNLL
2335



AP00431
Ref, human LLP 1
RVIEVVQGACRAIRHIPRRIRQGLE
2336



RIL




AP00432
Ref, human LLP
RIAGYGLRGLAVIIRICIRGLNLIFEI
2337



IR




AP00447
Ref, Anoplin
GLLKRIKTLL
2338


(insect)





AP00474
Ref, Piscidin 3
FIHHIFRGIVHAGRSIGRFLTG
2339


(fish)





AP00481
Ref, Kaliocin-1
FFSASCVPGADKGQFPNLCRLCAG
2340


(synthetic)
TGENKCA




AP00482
Ref, Thionin
KSCCRNTWARNCYNVCRLPGTISR
2341


mutation
EICAKKCRCKIISGTTCPSDYPK



(synthetic)





AP00484
Ref, Stomoxyn
RGFRKHFNKLVKKVKHTISETAHV
2342


(insect, fly)
AKDTAVIAGSGAAVVAAT




AP00486
Ref, Cupiennin 1b
GFGSLFKFLAKKVAKTVAKQAAK
2343


(spider)
QGAKYIANKQME




AP00487
Ref, Cupiennin 1c
GFGSLFKFLAKKVAKTVAKQAAK
2344


(spider)
QGAKYIANKQTE




AP00488
Ref, Cupiennin 1D
GFGSLFKFLAKKVAKTVAKQAAK
2345


(spider)
QGAKYVANKHME




AP00489
Ref, Hipposin
SGRGKTGGKARAKAKTRSSRAGL
2346


(fish)
QFPVGRVHRLLRKGNYAHRVGAG




APVYL




AP00923
Ref,
AISYGNGVYCNKEKCWVNKAENK
2347


Carnobacteriocin
QAITGIVIGGWASSLAGMGH



B1 (XXO, class Ha




bacteriocin,




bacteria)





AP00496
Ref, HP 2-20
AKKVFKRLEKLFSKIQNDK
2348


(synthetic)





AP00497
Ref, Maximin H5
ILGPVLGLVSDTLDDVLGIL
2349


(toad)





AP00498
Ref, rCRAMP (rat
GLVRKGGEKFGEKLRKIGQKIKEF
2350


cathelicidin)
FQKLALEIEQ




AP00500
Ref, S9-P18
KWKLFKKISKFLHLAKKF
2351


(synthetic)





AP00501
Ref, L9-P18
KWKLFKKILKFLHLAKKF
2352


(synthetic)





AP00502
Ref, Clavaspirin
FLRFIGSVIHGIGHLVHHIGVAL
2353


(sea squirt,




tunicate)





AP00503
Ref, human P-
AKRHHGYKRKFH
2354


113D





AP00504
Ref, human MUC7
LAHQKPFIRKSYKCLHKRCR
2355


20-Mer





AP00507
Ref, Nigrocin 2
GLLSKVLGVGKKVLCGVSGLC
2356


(frog)





AP00508
Ref, Nigrocin 1
GLLDSIKGMAISAGKGALQNLLKV
2357


(frog)
ASCKLDKTC




AP00509
Ref, human
VAIALKAAHYHTHKE
2358


Calcitermin





AP00510
Ref, Dicynthaurin
ILQKAVLDCLKAAGSSLSKAAITAI
2359


(sea peach)
YNKIT




AP00511
Ref, KIGAKI
KIGAKIKIGAKIKIGAKI
2360


(synthetic)





AP00516
Ref, Lycotoxin I
IWLTALKFLGKHAAKHLAKQQLS
2361


(spider)
KL




AP00517
Ref, Lycotoxin II
KIKWFKTMKSIAKFIAKEQMKKHL
2362


(spider)
GGE




AP00518
Ref, Ib-AMP3
QYRHRCCAWGPGRKYCKRWC
2363


(plant defensin,




balsam)





AP00519
Ref, Ib-AMP4
EWGRRCCGWGPGRRYCRRWC
2364


(plant defensin,




balsam)





AP00521
Ref, Dhvar4
KRLFKKLLFSLRKY
2365


(synthetic)





AP00522
Ref, Dhvar5
LLLFLLKKRKKRKY
2366


(synthetic)





AP00525
Ref, Maximin H2
ILGPVLSMVGSALGGLIKKI
2367


(toad)





AP00526
Ref, Maximin H3
ILGPVLGLVGNALGGLIKKI
2368


(toad)





AP00527
Ref, Maximin H4
ILGPVISKIGGVLGGLLKNL
2369


(toad)





AP00528
Ref, Anionic
DDDDDD
2370


peptide SAAP




(sheep)





AP00530
Ref, Lantibiotic
VLSKSLCTPGCITGPLQTCYLCFPT
2371


Ericin A (bacteria)
FAKC




AP00531
Ref, Kenoj einin I
GKQYFPKVGGRLSGKAPLAAKTH
2372


(sea skate)
RRLKP




AP00532
Ref, Lunatusin
KTCENLADTFRGPCFATSNC
2373


(plant, ZZHp)





AP00533
Ref, Fallaxin (frog)
GVVDILKGAAKDIAGHLASKVMN
2374



KL




AP00534
Ref, Tu-AMP 2
KSCCRNTTARNCYNVCRIPG
2375


(TuAMP2, thionin-




like antimicrobial




peptides, plant




defensin, tulip)





AP00535
Ref, Pilosulin 1
GLGSVFGRLARILGRVIPKVAKKL
2376


(Myr b I)
GPKVAKVLPKVMKEAIPMAVEMA



(Australian ants)
KSQEEQQPQ




AP00536
Ref, Luxuriosin
SVRTQDNAVNRQIFGSNGPYRDFQ
2377


(insect)
LSDCYLPLETNPYCNEWQFAYHW




NNALMDCERAIYHGCNRTRNNFIT




LTACKNQAGPICNRRRH




AP00537
Ref, SAMP H1
AEVAPAPAAAAPAKAPKKKAAAK
2378


(fish, Atlantic
PKKAGPS



salmon)





AP00538
Ref, Halocidin
WLNALLHHGLNCAKGVLA
2379


(dimer Hal18 +




Hal 15) (tunicate)





AP00539
Ref, AOD
GFGCPWNRYQCHSHCRSIGRLGGY
2380


(American oyster
CAGSLRLTCTCYRS



defensin, animal




defensin)





AP00540
Ref, Pentadactylin
GLLDTLKGAAKNVVGSLASKVME
2381


(frog)
KL




AP00541
Ref, Polybia-MPI
IDWKKLLDAAKQIL
2382


(insect, social




wasp)





AP00542
Ref, Polybia-CP
ILGTILGLLKSL
2383


(insect, social




wasp)





AP00543
Ref, Ocellatin-1
GVVDILKGAGKDLLAHLVGKISEK
2384


(XXA, frog)
V




AP00544
Ref, Ocellatin-2
GVLDIFKDAAKQILAHAAEKQI
2385


(XXA, frog)





AP00545
Ref, Ocellatin-3
GVLDILKNAAKNILAHAAEQI
2386


(frog)





AP00548
Ref, CMAP 27
RFGRFLRKIRRFRPKVTITIQGSARF
2387


(chicken myeloid
G



antimicrobial




peptide 27, bird




cathelicidin,




chicken




cathelicidin)





AP00550
Ref, Tu-AMP-1
KSCCRNTVARNCYNVCRIPGTPRP
2388


(TuAMP1, thionin-
VCAATCDCKLITGTKCPPGYEK



like antimicrobial




peptides, plant




defensin, tulip)





AP00551
Ref, Combi-2
FRWWHR
2389


(synthetic)





AP00552
Ref, Maximin 9
GIGRKFLGGVKTTFRCGVKDFASK
2390


(frog)
HLY




AP00554
Ref, Sl moricin
GKIPVKAIKKAGAAIGKGLRAINIA
2391


(insect)
STAHDVYSFFKPKHKKK




AP00555
Ref, Parasin I
KGRGKQGGKVRAKAKTRSS
2392


(catfish)





AP00556
Ref, Kassinatuerin-
GFMKYIGPLIPHAVKAISDLI
2393


1 (frog)





AP00557
Ref, Fowlicidin-1
RVKRVWPLVIRTVIAGYNLYRAIK
2394


(chCATH-1, bird
KK



cathelicidin,




chicken




cathelicidin)





AP00559
Ref, Eryngin
ATRVVYCNRRSGSVVGGDDTVYY
2395


(mushroom, fungi)
EG




AP00560
Ref, Dendrocin
TTLTLHNLCPYPVWWLVTPNNGG
2396


(plant, bamboo)
FPIIDNTPVVLG




AP00561
Ref, Coconut
EQCREEEDDR
2397


antifungal peptide




(plant)





AP00562
Ref, Pandinin 1
GKVWDWIKSAAKKIWSSEPVSQL
2398


(African scorpion)
KGQVLNAAKNYVAEKIGATPT




AP00563
Ref, White cloud
KTCENLADTFRGPCFATSNCDDHC
2399


bean defensin
KNKEHLLSGRCRDDFRCWCTRNC



(plant defensin)





AP00564
Ref, Dybowskin-1
FLIGMTHGLICLISRKC
2400


(frog)





AP00565
Ref, Dybowskin-2
FLIGMTQGLICLITRKC
2401


(frog)





AP00566
Ref, Dybowskin-3
GLFDVVKGVLKGVGKNVAGSLLE
2402


(frog)
QLKCKLSGGC




AP00567
Ref, Dybowskin-4
VWPLGLVICKALKIC
2403


(frog)





AP00568
Ref, Dybowskin-5
GLFSVVTGVLKAVGKNVAKNVGG
2404


(frog)
SLLEQLKCKKISGGC




AP00569
Ref, Dybowskin-6
FLPLLLAGLPLKLCFLFKKC
2405


(frog)





AP00570
Ref, Pleurain-A1
SIITMTKEAKLPQLWKQIACRLYNT
2406


(frog)
C




AP00571
Ref, Pleurai n-A2
SIITMTKEAKLPQSWKQIACRLYNT
2407


(frog)
C




AP00574
Ref, Esculentin-
GLFSKFAGKGIKNLIFKGVKHIGKE
2408


IGRa (frog)
VGMDVIRTGIDVAGCKIKGEC




AP00575
Ref, Brevinin-
GLLDTFKNLALNAAKSAGVSVLNS
2409


2GRa (frog)
LSCKLSKTC




AP00576
Ref, Brevinin-
GVLGTVKNLLIGAGKSAAQSVLKT
2410


2GRb (frog)
LSCKLSNDC




AP00577
Ref, Brevinin-
GLFTLIKGAAKLIGKTVAKEAGKT
2411


2GRc (frog)
GLELMACKITNQC




AP00578
Ref, Brevinin-
FLPLLAGLAANFLPKIFCKITKKC
2412


1GRa (frog)





AP00579
Ref, Nigrocin-
GLLSGILGAGKHIVCGLSGLC
2413


2GRa (frog)





AP00580
Ref, Nigrocin-
GLFGKILGVGKKVLCGLSGMC
2414


2GRb (frog)





AP00581
Ref, Nigrocin-
GLLSGILGAGKNIVCGLSGLC
2415


2GRc (frog)





AP00582
Ref, Brevinin-
GFSSLFKAGAKYLLKSVGKAGAQ
2416


2GHa (frog)
QLACKAANNCA




AP00583
Ref, Brevinin-
GVITDALKGAAKTVAAELLRKAH
2417


2GHb (frog)
CKLTNSC




AP00584
Ref, Guentherin
VIDDLKKVAKKVRRELLCKKHHK
2418


(frog)
KLN




AP00585
Ref, Brevinin-
SIWEGIKNAGKGFLVSILDKVRCK
2419


2GHc (frog)
VAGGCNP




AP00586
Ref, Temporin-GH
FLPLLFGAISHLL
2420


(frog)





AP00587
Ref, Brevinin-2T Sa
GIMSLFKGVLKTAGKHVAGSLVD
2421


(frog)
QLKCKITGGC




AP00588
Ref, Brevinin-1T Sa
FLGSIVGALASALPSLISKIRN
2422


(frog)





AP00589
Ref, Temporin-
FLGALAKIISGIF
2423


1T S a (frog)





AP00593
Ref, B revi nin-1CSa
FLPILAGLAAKIVPKLFCLATKKC
2424


(frog)





AP00594
Ref, Temporin-
FLPIVGKLLSGLL
2425


1CSa (frog)





AP00595
Ref, Temporin-
FLPIIGKLLSGLL
2426


1CSb (frog)





AP00596
Ref, Temporin-
FLPLVTGLLSGLL
2427


1CSc (frog)





AP00597
Ref, Temporin-
NFLGTLVNLAKKIL
2428


1CSd (frog)





AP00598
Ref, Temporin-
FLSAITSLLGKLL
2429


1SPb (frog)





AP00599
Ref, Brevinin-2-
GIWDTIKSMGKVFAGKILQNL
2430


related (frog)





AP00600
Ref, Odorranain-
GLLRASSVWGRKYYVDLAGCAKA
2431


HP (frog)





AP00601
Ref, Brevinin-
FLSLALAALPKFLCLVFKKC
2432


1DYa (frog)





AP00602
Ref, Brevinin-
FLSLALAALPKLFCLIFKKC
2433


1DYb (frog)





AP00603
Ref, Brevinin-
FLPLLLAGLPKLLCLFFKKC
2434


1DYc (frog)





AP00607
Ref, Brevinin-
GLFDVVKGVLKGAGKNVAGSLLE
2435


2DYb (frog)
QLKCKLSGGC




AP00608
Ref, Brevinin-
GLFDVVKGVLKGVGKNVAGSLLE
2436


2DYc (frog)
QLKCKLSGGC




AP00609
Ref, Brevinin-
GIFDVVKGVLKGVGKNVAGSLLE
2437


2DYd (frog)
QLKCKLSGGC




AP00610
Ref, Brevinin-
GLFSVVTGVLKAVGKNVAKNVGG
2438


2DYe (frog)
SLLEQLKCKISGGC




AP00611
Ref, Temporin-
FIGPIISALASLFG
2439


1DYa (frog)





AP00615
Ref, Palustrin-1b
ALFSILRGLKKLGNMGQAFVNCKI
2440


(frog)
YKKC




AP00616
Ref, Palustrin-1c
ALSILRGLEKLAKMGIALTNCKAT
2441


(frog)
KKC




AP00617
Ref, Palustrin-1d
ALSILKGLEKLAKMGIALTNCKAT
2442


(frog)
KKC




AP00619
Ref, Palustrin-2b
GFFSTVKNLATNVAGTVIDTLKCK
2443


(frog)
VTGGCRS




AP00620
Ref, Palustrin-2c
GFLSTVKNLATNVAGTVIDTLKCK
2444


(frog)
VTGGCRS




AP00621
Ref, Palustrin-3a
GIFPKIIGKGIKTGIVNGIKSLVKGV
2445


(frog)
GMKVFKAGLNNIGNTGCNEDEC




AP00622
Ref, Palustrin-3b
GIFPKIIGKGIKTGIVNGIKSLVKGV
2446


(frog)
GMKVFKAGLSNIGNTGCNEDEC




AP00624
Ref, human ALL-
ALLGDFFRKSKEKIGKEFKRIVQRI
2447


38 (an LL-37
KDFLRNLVPRTES



analog released




from its precursor




hCAP-18 by




gastricsin in vivo)





AP00625
Ref, human KR-20
KRIVQRIKDFLRNLVPRTES
2448


(KR20 from LL-




37)





AP00626
Ref, human KS-30
KSKEKIGKEFKRIVQRIKDFLRNLV
2449


(KS30 from LL-37)





PRTES




AP00627
Ref, human RK-31
RKSKEKIGKEFKRIVQRIKDFLRNL
2450


(RK31 from LL-
VPRTES



37)





AP00628
Ref, human LL-23
LLGDFFRKSKEKIGKEFKRIVQR
2451


(LL23 from LL-37)





AP00629
Ref, human LL-29
LLGDFFRKSKEKIGKEFKRIVQRIK
2452


(LL29 from LL-37)
DFLR




AP00630
Ref, Amoeba
GEILCNLCTGLINTLENLLTTKGAD
2453


peptide (protozoan




para





AP00631
Ref, Mundticin
KYYGNGVSCNKKGCSVDWGKAIG
2454


(bacteria)
IIGNNSAANLATGGAAGWSK




AP00638
Ref, Citropin 2.1
GLIGSIGKALGGLLVDVLKPKL
2455


(frog)





AP00639
Ref, Citropin 2.1.3
GLIGSIGKALGGLLVDVLKPKLQA
2456


(frog)
AS




AP00640
Ref, Maculatin 1.3
GLLGLLGSVVSHVVPAIVGHF
2457


(frog)





AP00641
Ref, Pardaxin 1
GFFALIPKIISSPLFKTLLSAVGSALS
2458


(Pardaxin P-1,
SSGEQE



Pardaxin P1, Pa1,




flat fish)





AP00642
Ref, Pardaxin 2
GFFALIPKIISSPIFKTLLSAVGSALS
2459


(Pardaxin P-2,
SSGGQE



Pardaxin P2,Pa2,




flat fish)





AP00643
Ref, Pardaxin 3
GFFAFIPKIISSPLFKTLLSAVGSALS
2460


(Pardaxin P-3,
SSGEQE



Pardaxin P3,Pa3,




flat fish)





AP00645
Ref, Pardaxin 5
GFFAFIPKIISSPLFKTLLSAVGSALS
2461


(Pardaxin P-5,
SSGDQE



Pardaxin P5, Pa5,




flat fish)





AP00647
Ref, Brevinin-1PLb
FLPLIAGLAANFLPKIFCAITKKC
2462


(frog)





AP00648
Ref, Brevinin-1PLc
FLPVIAGVAAKFLPKIFCAITKKC
2463


(frog)





AP00649
Ref, Esculentin-
GLFPKINKKKAKTGVFNIIKTVGKE
2464


1PLa (frog)
AGMDLIRTGIDTIGCKIKGEC




AP00650
Ref, Esculentin-
GIFTKINKKKAKTGVFNIIKTIGKEA
2465


1PLb (frog)
GMDVIRAGIDTISCKIKGEC




AP00651
Ref, Esculentin-
GLFSILKGVGKIALKGLAKNMGK
2466


2PLa (frog)
MGLDLVSCKISKEC




AP00652
Ref, Ranatuerin-
GIMDTVKNVAKNLAGQLLDKLKC
2467


2PLa (frog)
KITAC




AP00653
Ref, Ranatuerin-
GIMDTVKNAAKDLAGQLLDKLKC
2468


2PLb (frog)
RITGC




AP00654
Ref, Ranatuerin-
GLLDTIKNTAKNLAVGLLDKIKCK
2469


2PLc (frog)
MTGC




AP00655
Ref, Ranatuerin-
GIMDSVKNVAKNIAGQLLDKLKC
2470


2PLd (frog)
KITGC




AP00656
Ref, Ranatuerin-
GIMDSVKNAAKNLAGQLLDTIKCK
2471


2PLe (frog)
ITAC




AP00657
Ref, Ranatuerin-
GIMDTVKNAAKDLAGQLDKLKCR
2472


2PLf (frog)
ITGC




AP00658
Ref, Temporin-
FLPLVGKILSGLI
2473


1PLa (frog)





AP00659
Ref, Ranatuerin 5
FLPIASLLGKYL
2474


(frog)





AP00661
Ref, Esculentin-2L
GILSLFTGGIKALGKTLFKMAGKA
2475


(frog)
GAEHLACKATNQC




AP00662
Ref, Esculentin-2B
GLFSILRGAAKFASKGLGKDLTKL
2476


(ESC2B-RANBE,
GVDLVACKISKQC



frog)





AP00663
Ref, Esculentin-2P
GFSSIFRGVAKFASKGLGKDLARL
2477


(frog)
GVNLVACKISKQC




AP00664
Ref, Peptide A1
FLPAIAGILSQLF
2478


(frog)





AP00665
Ref, Peptide B9
FLPLIAGLIGKLF
2479


(frog)





AP00666
Ref, PG-L (frog)
EGGGPQWAVGHFM
2480



AP00667
Ref, PG-KI (frog)
EPHPDEFVGLM
2481



AP00668
Ref, PG-KIT (frog)
EPNPDEFVGLM
2482



AP00669
Ref, PG-KIII (frog)
EPHPNEFVGLM
2483



AP00670
Ref, PG-SPI (frog)
EPNPDEFFGLM
2484



AP00660
Ref, Pandinin 2
FWGALAKGALKLIPSLFSSFSKKD
2485


(African scorpion)





AP00671
Ref, PG-SPIT (frog)
EPNPNEFFGLM
2486



AP00673
Ref, Lantibiotic
WKSESVCTPGCVTGVLQTCFLQTI
2487


Ericin S (bacteria
TCNCHISK




AP00674
Ref, Lantibiotic
VLSKSLCTPGCITGPLQTCYLCFPT
2488


Ericin A (bacteria
FAKC




AP00675
Ref, Human beta
FELDRICGYGTARCRKKCRSQEYRI
2489


defensin 4 (HBD-4,
GRCPNTYACCLRKWDESLLNRTKP



HBD4, human




defensin)





AP00676
Ref, RL-37 (RL37,
RLGNFFRKVKEKIGGGLKKVGQKI
2490


monkey
KDFLGNLVPRTAS



cathelicidin)





AP00677
Ref, CAP11
GLRKKFRKTRKRIQKLGRKIGKTG
2491


(Guinea pig
RKVWKAWREYGQIPYPCRI



cathelicidin)





AP00678
Ref, Canine
RLKELITTGGQKIGEKIRRIGQRIKD
2492


cathelicidin
FFKNLQPREEKS



(K9CATH) (dog)





AP00679
Ref, Esculentin
GLFSILKGVGKIAIKGLGKNLGKM
2493


2VEb (frog)
GLDLVSCKISKEC




AP00680
Ref, SMAP-34
GLFGRLRDSLQRGGQKILEKAERI
2494


(sheep cathelicidin)
WCKIKDIFR




AP00681
Ref, OaBac5
RFRPPIRRPPIRPPFRPPFRPPVRPPIR
2495


(sheep cathelicidin)
PPFRPPFRPPIGPFP




AP00682
Ref, OaBac6
RRLRPRHQHFPSERPWPKPLPLPLP
2496


(sheep cathelicidin)
RPGPRPWPKPLPLPLPRPGLRPWPK




PL




AP00683
Ref, OaBac7.5
RRLRPRRPRLPRPRPRPRPRPRSLPL
2497


(sheep cathelicidin)
PRPQPRRIPRPILLPWRPPRPIPRP
Q I



QPIPRWL




AP00684
Ref, OaBac11
RRLRPRRPRLPRPRPRPRPRPRSLPL
2498


(sheep cathelicidin)
PRPKPRPIPRPLPLPRPRPKPIPRPLP




LPRPRPRRIPRPLPLPRPRPRPIPRPL




PLPQPQPSPIPRPL




AP00685
Ref, Ranatuerin
GIMDTVKGVAKTVAASLLDKLKC
2499




2VEb (frog)
KITGC


AP00686
Ref, eCATH-1
KRFGRLAKSFLRMRILLPRRKILLA
2500


(horse cathelicidin)
S




AP00687
Ref, eCATH-2
KRRHWFPLSFQEFLEQLRRFRDQL
2501


(horse cathelicidin)
PFP




AP00688
Ref, eCATH-3
KRFHSVGSLIQRHQQMIRDKSEAT
2502


(horse cathelicidin)
RHGIRIITRPKLLLAS




AP00689
Ref, P rop h eni n-1
AFPPPNVPGPRFPPPNFPGPRFPPPN
2503


(pig cathelicidin)
FPGPRFPPPNFPGPRFPPPNFPGPPFP




PPIFPGPWFPPPPPFRPPPFGPPRFP




AP00690
Ref, Prophenin-2
AFPPPNVPGPRFPPPNVPGPRFPPPN
2504


(pig cathelicidin)
FPGPRFPPPNFPGPRFPPPNFPGPPFP




PPIFPGPWFPPPPPFRPPPFGPPRFP


AP00691
Ref, HFIAP-1
GFFKKAWRKVKHAGRRVLDTAK
2505


(hagfish
GVGRHYVNNWLNRYR



cathelicidin)





AP00692
Ref, HFIAP-3
GWFKKAWRKVKNAGRRVLKGVG
2506


(hagfish
IHYGVGLI



cathelicidin)





AP00693
Ref, Trout cath
RICSRDKNCVSRPGVGSIIGRPGGG
2507


(fish cathelicidin)
SLIGRPGGGSVIGRPGGGSPPGGGS




FNDEFIRDHSDGNRFA




AP00694
Ref, MRP
AIGSILGALAKGLPTLISWIKNR
2508


(melittin-related




peptide)





AP00695
Ref, Temporin-
FLPILGKLLSGIL
2509


1TGa (frog)





AP00696
Ref, Dahlein 1.1
GLFDIIKNIVSTL
2510


(frog)





AP00697
Ref, Dahlein 1.2
GLFDIIKNIFSGL
2511


(frog)





AP00698
Ref, Dahlein 4.1
GLWQLIKDKIKDAATGFVTGIQS
2512


(frog)





AP00699
Ref, Dahlein 4.2
GLWQFIKDKLKDAATGLVTGIQS
2513


(frog)





AP00700
Ref, Dahlein 4.3
GLWQFIKDKFKDAATGLVTGIQS
2514


(frog)





AP00701
Ref, Dahlein 5.1
GLLGSIGNAIGAFIANKLKP
2515


(frog)





AP00702
Ref, Dahlein 5.2
GLLGSIGNAIGAFIANKLKPK
2516


(frog)





AP00703
Ref, Dahlein 5.3
GLLASLGKVLGGYLAEKLKP
2517


(frog)





AP00704
Ref, Dahlein 5.4
GLLGSIGKVLGGYLAEKLKPK
2518


(frog)





AP00705
Ref, Dahlein 5.5
GLLASLGKVLGGYLAEKLKPK
2519


(frog)





AP00706
Ref, Dahlein 5.6
GLLASLGKVFGGYLAEKLKPK
2520


(frog)





AP00709
Ref, Mytilus
GFGCPNDYPCHRHCKSIPGRAGGY
2521


defensin (mytilin)
CGGAHRLRCTCYR



A (mollusc)





AP00711
Ref, Mussel
GFGCPNNYACHQHCKSIRGYCGG
2522


defensin MGD2
YCAGWFRLRCTCYRCG




AP00712
Ref, scorpion
GFGCPLNQGACHRHCRSIRRRGGY
2523


defensin
CAGFFKQTCCYRN




AP00713
Ref, Androctonus
GFGCPFNQGACHRHCRSIRRRGGY
2524


defensin
CAGLFKQTCTCYR




AP00714
Ref, Orinthodoros
GYGCPFNQYQCHSHCSGIRGYKGG
2525


defensin A (soft
YCKGTFKQTCKCY



ticks)





AP00715
Ref, VaD1 (plant
RTCMKKEGWGKCLIDTTCAHSCK
2526


defensin)
NRGYIGGNCKGMTRTCYCLVNC




AP00722
Ref, Cryptonin
GLLNGLALRLGKRALKKIIKRLCR
2527


(insect, cicada)





AP00723
Ref, Decoralin
SLLSLLRKLIT
2528


(insect)





AP00724
Ref, RTD-2 (rhesus
RCLCRRGVCRCLCRRGVC
2529


theta-defensin-2,




minidefensin,




XXC, BBS, lectin,




ZZHa)





AP00725
Ref, RTD-3 (rhesus
RCICTRGFCRCICTRGFC
2530


theta-defensin-3,




minidefensin,




XXC, BBS, lectin,




ZZHa)





AP00726
Ref, Combi-1
RRWWRF
2531


(synthetic)





AP00748
Ref, Gm pro-rich
DIQIPGIKKPTHRDIIIPNWNPNVRT
2532


peptl (insect)
QPWQRFGGNKS




AP00749
Ref, Gm anionic
EADEPLWLYKGDNIERAPTTADHP
2533


pept 1 (insect)
ILPSIIDDVKLDPNRRYA




AP00750
Ref, Gm pro-rich
EIRLPEPFRFPSPTVPKPIDIDPILPHP
2534


pept 2 (insect)
WSPRQTYPIIARRS




AP00752
Ref, Gm defensin-
DKLIGSCVWGATNYTSDCNAECK
2535


like peptide (insect)
RRGYKGGHCGSFWNVNCWCEE




AP00753
Ref, Gm
VQETQKLAKTVGANLEETNKKL
A 2536


apolipophoricin
PQIKSAYDDFVKQAQEVQKKLHE



(insect)
AASKQ




AP00754
Ref, Gm anionic
ETESTPDYLKNIQQQLEEYTKNFNT
2537


pept2 (insect)
QVQNAFDSDKIKSEVNNFIESLGKI




LNTEKKEAPK




AP00755
Ref, Gm cecropin
ENFFKEIERAGQRIRDAIISAAPAVE
2538


D-like pept,insect
TLAQAQKIIKGGD




AP00756
Ref, Dermaseptin-
ALWKDILKNAGKAALNEINQLVN
2539


B6 (DRS-B6, DRS
Q



B6, XXA, frog)





AP00759
Ref, Phylloseptin-
FLSLIPHAINAVSTLVHHSG
2540


O1 (PLS-O1,




Phylloseptin-4, PS-




4, XXA, frog)





AP00760
Ref, Phylloseptin-
FLSLIPHAINAVSAIAKHS
2541


O2 (PLS-O2,




Phylloseptin-5, PS-




5, XXA, frog)





AP00761
Ref, Phylloseptin-6
SLIPHAINAVSAIAKHF
2542


(Phylloseptin-H4,




PLS-H4, PS-6,




XXA, frog)





AP00762
Ref, Phylloseptin-7
FLSLIPHAINAVSAIAKHF
2543


(Phylloseptin-H5,




PLS-H5, PS-7,




XXA, frog)





AP00763
Ref, Dermaseptin
GLWSTIKNVGKEAAIAAGKAALG
2544


DPh-1 (XXA, frog)
AL




AP00764
Ref, Dermaseptin-
GLRSKIWLWVLLMIWQESNKFKK
2545


S9 (DRS-S9, DRS
M



S9, frog)





AP00765
Ref, Human salvic
MHDFWVLWVLLEYIYNSACSVLS
2546



ATSSVSSRVLNRSLQVKVVKITN




AP00766
Ref, Gassericin A
IYWIADQFGIHLATGTARKLLDAM
2547


(XXC, XXD2,
ASGASLGTAFAAILGVTLPAWALA



class IV
AAGALGATAA



bacteriocin, Gram-




positive bacteria)





AP00767
Ref, Circularin
AVAGALGVQTAAATTIVNVILNAGT
2548


(XXC, class IV
LVTVLGIIASIASGGAGTLMTIGWA



bacteriocin, Gram-
TFKATVQKLAKQSMARAIAY



positive bacteria)





AP00768
Ref, Closticin 574
PNWTKIGKCAGSIAWAIGSGLFGG
2549


(bacteria)
AKLIKIKKYIAELGGLQKAAKLLV




GATTWEEKLHAGGYALINLAAELT




GVAGIQANCF




AP00769
Ref, Caerin 1.11
GLLGAMFKVASKVLPHVVPAITEH
2550


(XXA, frog)
F




AP00770
Ref, Maculatin 1.4
GLLGLLGSVVSHVLPAITQHL
2551


(XXA, frog)





AP00771
Ref, Magainin 1
GIGKFLHSAGKFGKAFVGEIMKS
2552


(frog)





AP00772
Ref, Oxyopinin 1
FRGLAKLLKIGLKSFARVLKKVLP
2553


(spider)
KAAKAGKALAKSMADENAIRQQN




Q




AP00773
Ref, Oxyopinin 2a
GKFSVFGKILRSIAKVFKGVGKVR
2554


(spider)
KQFKTASDLDKNQ




AP00774
Ref, Oxyopinin 2b
GKFSGFAKILKSIAKFFKGVGKVR
2555


(spider)
KGFKEASDLDKNQ




AP00775
Ref, Oxyopinin 2c
GKLSGISKVLRAIAKFFKGVGKAR
2556


(spider)
KQFKEASDLDKNQ




AP00776
Ref, Oxyopinin 2d
GKFSVFSKILRSIAKVFKGVGKVRK
2557


(spider)
GFKTASDLDKNQ




AP00777
Ref, NRC-1 (XXA,
GKGRWLERIGKAGGIIIGGALDHL
2558


fish, gene




predicted)





AP00778
Ref, NRC-2 (XXA,
WLRRIGKGVKIIGGAALDHL
2559


fish, gene




predicted)





AP00779
Ref, NRC-3 (XXA,
GRRKRKWLRRIGKGVKIIGGAALD
2560


fish, gene
HL



predicted)





AP00781
Ref, NRC-5 (XXA,
FLGALIKGAIHGGRFIHGMIQNHH
2561


fish, gene




predicted)





AP00782
Ref, NRC-6 (XXA,
GWGSIFKHGRHAAKHIGHAAVNH
2562


fish, gene
YL



predicted)





AP00783
Ref, NRC-7 (XXA,
RWGKWFKKATHVGKHVGKAALT
2563


fish, gene
AYL



predicted)





AP00784
Ref, NRC-10
FFRLLFHGVHHVGKIKPRA
2564


(XXA, fish, gene




predicted)





AP00785
Ref, NRC-11
GWKSVFRKAKKVGKTVGGLALD
2565


(XXA, fish, gene
HYL



predicted)





AP00786
Ref, NRC-12
GWKKWFNRAKKVGKTVGGLAVD
2566


(XXA, fish, gene
HYL



predicted)





AP00787
Ref, NRC-13
GWRLLLKKAEVKTVGKLALKHYL
2567


(XXA, fish, gene




predicted)





AP00788
Ref, NRC-14
AGWGSIFKHIFKAGKFIHGAIQAHN
2568


(XXA, fish, gene
D



predicted)





AP00789
Ref, NRC-15
GFWGKLFKLGLHGIGLLHLHL
2569


(XXA, fish, gene




predicted)





AP00790
Ref, NRC-16
GWKKWLRKGAKHLGQAAIK
2570


(XXA, fish, gene




predicted)





AP00791
Ref, NRC-17
GWKKWLRKGAKHLGQAAIKGLA
2571


(XXA, fish, gene
S



predicted)





AP00792
Ref, NRC-19
FLGLLFHGVHHVGKWIHGLIHGHH
2572


(XXA, fish, gene




predicted)





AP00793
Ref, Bombinin H2
IIGPVLGLVGSALGGLLKKI
2573


(XXA, frog)





AP00794
Ref, Bombinin H3
IIGPVLGMVGSALGGLLKKI
2574


(frog, XXD, XXA)





AP00795
Ref, Bombinin H7
ILGPILGLVSNALGGLL
2575


(frog, XXD, XXA)





AP00796
Ref, Bombinin GH-
IIGPVLGLVGKPLESLLE
2576


1L (XXA, toad)





AP00797
Ref, Bombinin GH-
IIGPVLGLVGKPLESLLE
2577


1D (toad,XXD,




XXA)





AP00807
Ref, Enterocin E-
NRWYCNSAAGGVGGAAGCVLAG
2578


760 (bacteriocin,
YVGEAKENIAGEVRKGWGMAGGF



bacteria)
THNKACKSFPGSGWASG




AP00808
Ref, hepcidin (fish)
CRFCCRCCPRMRGCGLCCRF
2579



AP00809
Ref, hepcidin TH1-
GIKCRFCCGCCTPGICGVCCRF
2580


5 (fish)





AP00810
Ref, hepcidin TH2-
QSHLSLCRWCCNCCRSNKGC
2581


3 (fish)





AP00811
Ref, human LEAP-
MTPFWRGVSLRPIGASCRDDSECIT
2582


2
RLCRKRRCSLSVAQE




AP00812
Ref, Enkelytin
FAEPLPSEEEGESYSKEPPEMEKRY
2583


(cow)
GGFM




AP00732
Ref, Spheniscin-1
SFGLCRLRRGSCAHGRCRFPSIPIG
2584


(Sphe-1, avian
RCSRFVQCCRRVW



defensin)





AP00733
Ref, Organgutan
LLGDFFRKAREKIGEEFKRIVQRIK
2585


ppyLL-37 (Great
DFLRNLVPRTES



Ape, primate




cathelicidin)





AP00734
Ref, Gibbon
SLGNFFRKARKKIGEEFKRIVQRIK
2586


hmdSL-37
DFLQHLIPRTEA



(hylobatidae,




primate




cathelicidin)





AP00735
Ref, pobRL-37
RLGNFFRKAKKKIGRGLKKIGQKI
2587


(cercopithecidae,
KDFLGNLVPRTES



primate




cathelicidin)





AP00736
Ref, cjaRL-37
RLGDILQKAREKIEGGLKKLVQKI
2588


(primate
KDFFGKFAPRTES



cathelicidin)





AP00737
Ref, Plasticin
GLVTSLIKGAGKLLGGLFGSVTG
2589


PBN2KF (XXA,




DRP-PBN2, frog)





AP00738
Ref, Plasticin
GLVTGLLKTAGKLLGDLFGSLTG
2590


ANCKF (XXA,




synthetic)





AP00739
Ref, Plasticin
GVVTDLLKTAGKLLGNLFGSLSG
2591


PD36KF (XXA,




synthetic)





AP00740
Ref, Plasticin
GVVTDLLKTAGKLLGNLVGSLSG
2592


PD36K (XXA,




synthetic)





AP00741
Ref, Chicken
PITYLDAILAAVRLLNQRISGPCILR
2593


cathelicidin-B1
LREAQPRPGWVGTLQRRREVSFLV



(bird cathelicidin)
EDGPCPPGVDCRSCEPGALQHCVG




TVSIEQQPTAELRCRPLRPQ




AP00742
Ref, Chicken
MRILYLLLSVLFVVLQGVAGQPYF
2594


gallinacin 4 (Gal 4)
SSPIHACRYQRGVCIPGPCRWPYY




RVGSCGSGLKSCCVRNRWA




AP00743
Ref, Chicken
MKILCFFIVLFVAVHGAVGFSRSPR
2595


gallinacin 7 (Gal 7)
YHMQCGYRGTFCTPGKCPYGNAY




LGLCRPKYSCCRWL




AP00744
Ref, Chicken
MQILPLLFAVLLLMLRAEPGLSLA
2596


gallinacin 9 (Gal 9)
RGLPQDCERRGGFCSHKSCPPGIGR




IGLCSKEDFCCRSRWYS




AP00745
Ref, Chicken
MTPFWRGVSLRPVGASCRDNSECI
2597


LEAP-2 (cLEAP-
TMLCRKNRCFLRTASE



2)





AP00814
Ref, Caerulein
GLGSILGKILNVAGKVGKTIGKVA
2598


precursor-related
DAVGNKE



fragment Ea




(CPRF-Ea, frog)





AP00815
Ref, Caerulein
GLGSFLKNAIKIAGKVGSTIGKVAD
2599


precursor-related
AIGNKE



fragment Eb




(CPRF-Eb, frog)





AP00816
Ref, Caerulein
GLGSFFKNAIKIAGKVGSTIGKVAD
2600


precursor-related
AIGNKE



fragment Ec




(CPRF-Ec, frog)





AP00817
Ref, Temporin-10a
FLPLLASLFSRLL
2601


(frog)





AP00818
Ref, Temporin-10b
FLPLIGKILGTIL
2602


(frog)





AP00819
Ref, Temporin-10c
FLPLLASLFSRLF
2603


(frog)





AP00820
Ref, Temporin-10d
FLPLLASLFSGLF
2604


(frog)





AP00821
Ref, Brevinin-20a
GLFNVFKGLKTAGKHVAGSLLNQ
2605


(frog)
LKCKVSGGC




AP00822
Ref, Brevinin-20b
GIFNVFKGALKTAGKHVAGSLLNQ
2606


(frog)
LKCKVSGEC




AP00824
Ref, Temporin-1Gb
SILPTIVSFLSKFL
2607


(XXA, frog)





AP00825
Ref, Temporin-1Gc
SILPTIVSFLTKFL
2608


(XXA, frog)





AP00826
Ref, Temporin-1Gd
FILPLIASFLSKFL
2609


(XXA, frog)





AP00827
Ref, Ranatuerin-
SMISVLKNLGKVGLGFVACKVNK
2610


1Ga (frog)
QC




AP00829
Ref, Ranalexin-1G
FLGGLMKIIPAAFCAVTKKC
2611


(frog)





AP00830
Ref, Ranatuerin-2G
GLLLDTLKGAAKDIAGIALEKLKC
2612


(frog)
KITGCKP




AP00831
Ref, Odorranain-
GLLSGILGAGKHIVCGLTGCAKA
2613


NR (frog)





AP00832
Ref, Maximin H1
ILGPVISTIGGVLGGLLKNL
2614


(XXA, toad)





AP00834
Ref, G. mellonella
KVNANAIKKGGKAIGKGFKVISAA
2615


moricin-like
STAHDVYEHIKNRRH



peptide A (Gm-




mlpA, insect)





AP00835
Ref, G. mellonella
GKIPVKAIKKGGQIIGKALRGINIAS
2616


moricin-like
TAHDIISQFKPKKKKNH



peptide B (Gm-




m1pB, insect)





AP00836
Ref, G. mellonella
KVPIGAIKKGGKIIKKGLGVIGAAG
2617


moricin-like
TAHEVYSHVKNRH



peptide Cl (Gm-




m1pC1, insect)





AP00837
Ref, G. mellonella
KVPIGAIKKGGKIIKKGLGVLGAA
2618


moricin-like
GTAHEVYNHVRNRQ



peptide C2 (Gm-




m1pC2, insect)





AP00838
Ref, G. mellonella
KVPIGAIKKGGKIIKKGLGVIGAAG
2619


moricin-like
TAHEVYSHVKNRQ



peptide C3 (Gm-




m1pC3, insect)





AP00839
Ref, G. mellonella
KVPVGAIKKGGKAIKTGLGVVGA
2620


moricin-like
AGTAHEVYSHIRNRH



peptide C4/C5




(Gm-m1pC4/C5,




insect)





AP00840
Ref, G. mellonella
KGIGSALKKGGKIIKGGLGALGAIG
2621


moricin-like
TGQQVYEHVQNRQ



peptide D (Gm-




m1pD, insect)





AP00841
Ref, Enterocin A
TTHSGKYYGNGVYCTKNKCTVD
2622


(EntA, class IIA
WAKATTCIAGMSIGGFLGGAIPGK



bacteriocin, i.e.
C



pediocin-like




peptide, bacteria)





AP00842
Ref, Divercin V41
TKYYGNGVYCNSKKCWVDWGQA
2623


(DvnV41, class IIa
SGCIGQTVVGGWLGGAIPGKC



bacteriocin,




pediocin-like




peptide, bacteria.




DvnRV41 is the




recombinant form)





AP00843
Ref, Divergicin
TKYYGNGVYCNSKKCWVDWGTA
2624


M35 (class IIa
QGCIDVVIGQLGGGIPGKGKC



bacteriocin,




pediocin-like




peptide, bacteria)





AP00844
Ref, Coagulin
KYYGNGVTCGKHSCSVDWGKATT
2625


(bacteriocin,
CIINNGAMAWATGGHQGTHKC



pediocin-like




peptide, bacteria)





AP00845
Ref, Listeriocin
KSYGNGVHCNKKKCWVDWGSAIS
2626


743A (class IIa
TIGNNSAANWATGGAAGWKS



bacteriocin,




pediocin-like




peptide, bacteria)





AP00846
Ref, Mundticin
KSKYYGNGVSCNKKGCSVDWGKAIG
2627


(enterocin CRL35,
IIGNNSAANLATGGAAGWKS



mundticin ATO6,




mundticin QU2,




class IIa




bacteriocin,




pediocin-like




peptide, bacteria)





AP00847
Ref, Sakacin 5X
KYYGNGLSCNKSGCSVDWSKAISII
2628


(Sak5X, class IIa
GNNAVANLTTGGAAGWKS



bacteriocin,




pediocin-like




peptide, bacteria)





AP00848
Ref, Leucocin
CKNYGNGVHCTKKGCSVDWGYAW
2629


(class IIa
ANIANNSVMNGLTGGNAGWHN



bacteriocin,




pediocin-like




peptide, bacteria)





AP00849
Ref, Lactococcin
TSYGNGVHCNKSKCWIDVSELETY
2630


MMFII (class IIa
KAGTVSNPKDILW



bacteriocin,




pediocin-like




peptide, bacteria)





AP00850
Ref, Sakacin G
KYYGNGVSCNSHGCSVNWGQAW
2631


(SakG, class IIa
TCGVNHLANGGHGVC



bacteriocin,




pediocin-like




peptide, bacteria)





AP00851
Ref, Plantaricin
KYYGNGVTCGKHSCSVNWGQAFS
2632


423 (class IIa
CSVSHLANFGHGKC



bacteriocin,




pediocin-like




peptide, bacteria)





AP00852
Ref, Plantaricin
KYYGNGLSCSKKGCTVNWGQAFS
2633


C19 (class IIa
CGVNRVATAGHHKC



bacteriocin,




pediocin-like




peptide, bacteria)





AP00853
Ref, Enterocin P
ATRSYGNGVYCNNSKCWVNWGE
2634


(EntP, class IIa
AKENIAGIVISGWASGLAGMGH



bacteriocin,




pediocin-like




peptide, bacteria)





AP00854
Ref, Bacteriocin 31
ATYYGNGLYCNKQKCWVDWNKA
2635


(Bac31, Bac31,
SREIGKIIVNGWVQHGPWAPR



class IIa




bacteriocin,




pediocin-like




peptide, bacteria)





AP00855
Ref, MSI-78
GIGKFLKKAKKFGKAFVKILKK
2636


(XXA, synthetic)





AP00856
Ref, MSI-594
GIGKFLKKAKKGIGAVLKVLTTGL
2637


(XXA, synthetic)





AP00857
Ref, Catestatin
SSMKLSFRARAYGFRGPGPQL
2638


(human




CHGA(352-372),




human Cst)





AP00858
Ref, Temporin D
LLPIVGNLLNSLL
2639


(XXA, frog)





AP00859
Ref, Temporin H
LSPNLLKSLL
2640


(XXA, frog)





AP00861
Ref, Brevinin-ALb
FLPLAVSLAANFLPKLFCKITKKC
2641


(frog)





AP00862
Ref, Brevinin 1E
FLPLLAGLAANFLPKIFCKITKRC
2642


(frog)





AP00863
Ref, Temporin-
FLPIVGKLLSGLSGLL
2643


ALa (XXA, frog)





AP00864
Ref, Temporin
FLPIVGRLISGLL
2644


1ARa (XXA, frog)





AP00865
Ref, Temporin
FLPIIGQLLSGLL
2645


1AUa (XXA,




Temporin-lAtJa)




(frog)





AP00866
Ref, Temporin
FLPIIAKVLSGLL
2646


1Bya (XXA,




Temporin-lBya,




frog)





AP00867
Ref, Temporin 1Ec
FLPVIAGLLSKLF
2647


(XXA, frog)





AP00869
Ref, Temporin 1Ja
ILPLVGNLLNDLL
2648


(XXA, Temporin-




1Ja, frog)





AP00873
Ref, Temporin 1Pra
ILPILGNLLNGLL
2649


(XXA, frog)





AP00874
Ref, Temporin 1VE
FLPLVGKILSGLI
2650


(XXA, frog)





AP00875
Ref, Temporin 1Va
FLSSIGKILGNLL
2651


(XXA, frog)





AP00876
Ref, Temporin 1Vb
FLSIIAKVLGSLF
2652


(XXA, frog)





AP00877
Ref, Brevinin-lJa
FLGSLIGAAIPAIKQLLGLKK
2653


(frog)





AP00878
Ref, Brevinin-
FLPILASLAAKFGPKLFCLVTKKC
2654


1BYa (frog)





AP00884
Ref, Ixosin-B (tick)
QLKVDLWGTRSGIQPEQHSSGKSD
2655



VRRWRSRY




AP00885
Ref, Brevinin-
FLPILASLAAKLGPKLFCLVTKKC
2656


1BYb (frog)





AP00886
Ref, Brevinin-
FLPILASLAATLGPKLLCLITKKC
2657


1BYc (frog)





AP00887
Ref, Brevinin-
GILSTFKGLAKGVAKDLAGNLLDK
2658


2BYa (frog)
FKCKITGC




AP00888
Ref, Brevinin-
GIMDSVKGLAKNLAGKLLDSLKC
2659


2BYb (frog)
KITGC




AP00891
Ref, Pilosulin 3
IIGLVSKGTCVLVKTVCKKVLKQG
2660


(Myr b III)(ants)





AP00892
Ref, Pilosulin 4
PDITKLNIKKLTKATCKVISKGASM
2661


(Myr b IV)(ants)
CKVLFDKKKQE




AP00893
Ref, Pilosulin 5
DVKGMKKAIKGILDCVIEKGYDKL
2662


(Myr b III)(ants)
AAKLKKVIQQLWE




AP00894
Ref, Ocellatin 4
GLLDFVTGVGKDIFAQLIKQI
2663


(XXA, frog)





AP00895
Ref, OH-CATH
KRFKKFFKKLKNSVKKRAKKFFK
2664


(snake cathelicidin,
KPRVIGVSIPF



reptile cathelicidin,




or elapid




cathelicidins)





AP00896
Ref, BF-CATH
KRFKKFFKKLKKSVKKRAKKFFK
2665


(snake cathelicidin)
KPRVIGVSIPF




AP00897
Ref, NA-CATH
KRFKKFFKKLKNSVKKRAKKFFK
2666


(snake cathelicidin)
KPKVIGVTFPF




AP00898
Ref, Temporin-1Sa
FLSGIVGMLGKLF
2667


(XXA, frog)





AP00899
Ref, Temporin-1Sb
FLPIVTNLLSGLL
2668


(XXA, frog)





AP00900
Ref, Temporin-1Sc
FLSHIAGFLSNLF
2669


(XXA, frog)





AP00913
Ref, Ib-AMP1
EWGRRCCGWGPGRRYCVRWC
2670


(IbAMP1, plant




defensin)





AP00914
Ref, Ib-AMP2
QYGRRCCNWGPGRRYCKRWC
2671


(IBAMP2, plant




defensin)





AP00915
Ref, Ee-CBP
QQCGRQAGNRRCANNLCCSQYGY
2672


(EeCBP, plant
CGRTNEYCCTSQGCQSQCRRCG



defensin, hevein-




type, E. europaeus




chitin-binding




protein)





AP00916
Ref, Pa-AMP1
AGCIKNGGRCNASAGPPYCCSSYC
2673


(PaAMP1, plant
FQIAGQSYGVCKNR



defensin, C6 type)





AP00917
Ref, Pa-AMP2
ACIKNGGRCVASGGPPYCCSNYCL
2674


(PaAMP2, plant
QIAGQSYGVCKKH



defensin, C6 type)





AP00924
Ref, Ornithodoros
GYGCPFNQYQCHSHCRGIRGYKG
2675


defensin B (soft
GYCTGRFKQTCKCY



ticks)





AP00925
Ref, Ornithodoros
GYGCPFNQYQCHSHCSGIRGYKGG
2676


defensin C (soft
YCKGLFKQTCNCY



ticks)





AP00926
Ref, Ornithodoros
GFGCPFNQYECHAHCSGVPGYKG
2677


defensin D (soft
GYCKGLFKQTCNCY



ticks)





AP00927
Ref,
IYFIADKMGIQLAPAWYQDIVNWV
2678



Butyrivibriocin

SAGGTLTTGFAIIVGVTVPAWIAEA



AR10 (XXC, class
AAAFGIASA



IV bacteriocin,




gram-positive




bacteria)





AP00929
Ref, AS-48
ASLQFLPIAHMAKEFGIPAAVAGT
2679


(enterocin 4, XXC,
VINVVEAGGWVTTIVSILTAVGSG



class IV bacteriocin
GLSLLAAAGRESIKAYLKKEIKKK



or class lid
GKRAVIAW



bacteriocin, Gram-




positive bacteria)





AP00930
Ref, Reutericin 6
IYWIADQFGIHLATGTARKLLDAM
2680


(XXC, XXD1,
ASGASLGTAFAAILGVTLPAWALA



class IV
AAGALGATAA



bacteriocin, Gram-




positive bacteria)





AP00931
Ref, Uberolysin
LAGYTGIASGTAKKVVDAIDKGAA
2681


(XXC, class IV
AFVIISIISTVISAGALGAVSASADFI



bacteriocin, Gram-
ILTVKNYISRNLKAQAVIW



positive bacteria)





AP00932
Ref, Acidocin B
IYWIADQFGIHLATGTARKLLDAV
2682


(XXC, class IV
ASGASLGTAFAAILGVTLPAWALA



bacteriocin, Gram-
AAGALGATAA



positive bacteria)





AP00980
Ref, Phormia
ATCDLLSGTGINHSACAAHCLLRG
2683


defensin B (insect
NRGGYCNRKGVCVCRN



defensin B)





AP00990
Ref, Pth-St1 (plant
RNCESLSHRFKGPCTRDSN
2684


defensin)





AP00991
Ref, Snakin-1
GSNFCDSKCKLRCSKAGLADRCLK
2685


(StSN1, plant
YCGICCEECKCVPSGTYGNKHECP



defensin)
CYRDKKNSKGKSKCP




AP00992
Ref, Snakin-2
YSYKKIDCGGACAARCRLSSRPRL
2686


(StSN2, plant
CNRACGTCCARCNCVPPGTSGNTE



defensin)
TCPCYASLTTHGNKRKCP




AP00993
Ref, So-D2 ( S.
GIFSSRKCKTPSKTFKGICTRDSNC
2687


oleracea defensin
DTSCRYEGYPAGDCKGIRRRCMCS



D2, plant defensin)
KPC




AP00994
Ref, So-D6 ( S.
GIFSNMYARTPAGYFRGP
2688


oleracea defensin




D6, plant defensin)





AP00997
Ref, Nisin Q
ITSISLCTPGCKTGVLMGCNLKTAT
2689


(lantibiotic,
CNCSVHVSK



bacteriocins,




bacteria)





AP01008
Ref, Tachystatin
YSRCQLQGFNCVVRSYGLPTIPCC
2690


A1 (BBS,
RGLTCRSYFPGSTYGRCQRF



horseshoe crabs)





AP01009
Ref, Tachystatin C
DYDWSLRGPPKCATYGQKCRTWS
2691


(BBS, horseshoe
PRNCCWNLRCKAFRCRPR



crabs)





AP01012
Ref, Latarcin 3a
SWKSMAKKLKEYMEKLKQRA
2692


(Ltc3a, XXA,




BBM, spider)





AP01013
Ref, Latarcin 3b
SWASMAKKLKEYMEKLKQRA
2693


(Ltc3b, XXA,




BBM, spider)





AP01014
Ref, Latarcin 4a
GLKDKFKSMGEKLKQYIQTWKAK
2694


(Ltc4a, XXA,
F



BBM, spider)





AP01015
Ref, Latarcin 4b
SLKDKVKSMGEKLKQYIQTWKAK
2695


(Ltc4b, XXA,
F



BBM, spider)





AP01016
Ref, Latarcin 5
GFFGKMKEYFKKFGASFKRRFANL
2696


(Ltc5, XXA, BBM,
KKRL



spider)





AP01018
Ref, Latarcin 6a
QAFQTFKPDWNKIRYDAMKMQTS
2697


(Ltc6a, BBM,
LGQMKKRFNL



spider)





AP01019
Ref, Latarcin 7
GETFDKLKEKLKTFYQKLVEKAED
2698


(Ltc7, BBM,
LKGDLKAKLS



spider)





AP01049
Ref, Kalata B2
VCGETCFGGTCNTPGCSCTWPICT
2699


(plant cyclotides,
RDGLP



XXC)





AP01141
Ref, Cryptdin -6
LRDLVCYCRARGCKGRERMNGTC
2700


(Crp6, animal
RKGHLLYMLCCR



defensin, alpha,




mouse)





AP01142
Ref, Rabbit kidney
KPYCSCKWRCGIGEEEKGICHKFPI
2701


defensin RK-2
VTYVCCRRP



(animal defensin,




alpha-defensin)





AP01146
Ref, Gallinacin 6
DTLACRQSHGSCSFVACRAPSVDI
2702


(Gal6, Gal-6, avian
GTCRGGKLKCCKWAPSS



beta defensin, bird)





AP01147
Ref, Gallinacin 8
DTVACRIQGNFCRAGACPPTFTISG
2703


(Gal8, Gal-8, avian
QCHGGLLNCCAKIPAQ



beta defensin, bird)





AP01148
Ref, Gallinacin 3
IATQCRIRGGFCRVGSCRFPHIAIGK
2704


(Gal3, Gal-3, avian
CATFISCCGRAY



beta defensin, bird)





AP01152
Ref, Lactococcin Q
SIWGDIGQGVGKAAYWVGKAMG
2705


(class IIb
NMSDVNQASRINRKKKH



bacteriocin,




bacteria, chain a.




For chain b, see




Info)





AP01155
Ref, Enterocin
ESVFSKIGNAVGPAAYWILKGLGN
2706


1071 (Ent1071A,
MSDVNQADRINRKKH



class IIb




bacteriocin,




bacteria; chain B is




Enterocin 1071B or




Ent1071B, see




info)





AP01156
Ref, Plantaricin S
NKLAYNMGHYAGKATIFGLAAW
2707


(chain a, class IIb
ALLA



bacteriocin,




bacteria)





AP01159
Ref, Hinnavin II
KWKIFKKIEHMGQNIRDGLIKAGP
2708


(Hin II, XXA,
AVQVVGQAATIYK



insect)





AP01160
Ref, NK-2
KILRGLCKKIMRSFLRRISWDILTG
2709


(synthetic, XXA)
KK




AP01167
Ref, Plantaricin
LTTKLWSSWGYYLGKKARWNLK
2710


NC8 (PLNC8,
HPYVQF



chain a, class IIb




bacteriocin,




bacteria. For chain




b, see Info)





AP01168
Ref, Carnocyclin A
LVAYGIAQGTAEKVVSLINAGLTV
2711


(a circular
GSIISILGGVTVGLSGVFTAVKAAI



bacteriocin, XXC,
AKQGIKKAIQL



bacteria)





AP01169
Ref, Lactacin F
NRWGDTVLSAASGAGTGIKACKSF
2712


(LafX, class IIb
GPWGMAICGVGGAAIGGYFGYTH



bacteriocin,
N



bacteria. For LafA,




see Info)





AP01170
Ref, Brochocin C
YSSKDCLKDIGKGIGAGTVAGAAG
2713


(BrcC, chain BrcA,
GGLAAGLGAIPGAFVGAHFGVIGG



class IIb
SAACIGGLLGN



bacteriocin,




bacteria. For BrcB,




see Info)





AP01171
Ref, Thermophilin
YSGKDCLKDMGGYALAGAGSGAL
2714


13 (chain a ThmA,
WGAPAGGVGALPGAFVGAHVGAI



2-chain class IIb
AGGFACMGGMIGNKFN



bacteriocin,




bacteria. For chain




B ThmB, see Info)





AP01172
Ref, ABP-118
KRGPNCVGNFLGGLFAGAAAGVP
2715


(chain a:
LGPAGIVGGANLGMVGGALTCL



Abp118alpha, class




IIb bacteriocin,




bacteria. For chain




b: Abp118beta, see




Info)





AP01173
Ref, Salivaricin P
KRGPNCVGNFLGGLFAGAAAGVP
2716


(chain a: Sln1;
LGPAGIVGGANLGMVGGALTCL



class IIb




bacteriocin,




bacteria. For chain




b: Sln2, see Info)





AP01174
Ref, Mutacin IV
KVSGGEAVAAIGICATASAAIGGL
2717


(chain a: NlmA,
AGATLVTPYCVGTWGLIRSH



class IIb




bacteriocin,




bacteria. For chain




b:NLmB, see Info)





AP01175
Ref, Lactocin 705
GMSGYIQGIPDFLKGYLHGISAAN
2718


(chain a:
KHKKGRLGY



Lac705alpha; class




IIb bacteriocin,




bacteria. For chain




b: Lac705beta, see




Info)





AP01176
Ref, Cytolysin
TTPACFTIGLGVGALFSAKFC
2719


(CylLS, bacteria;




Chain B: CylLL)





AP01177
Ref, Plantaricin
EFFNRGGYNFGKSVRHVVDAIGSVA
2720


(chain a: PlnE,
GILKSIR



class IIb




bacteriocin,




bacteria. Chain b:




PlnF)





AP01178
Ref, Plantaricin
JKGAWKNFWSSLRKGFYDGEAGRAI
2721


(chain a: PlnJ; class
RR



IIb bacteriocin,




bacteria. Chain b:




PlnK)





AP01179
Ref, Enterocin SE-
NGVYCNKQKCWVDWSRARSEIID
2722


K4 (class IIa
RGVKAYVNGFTKVLGGIGGR



bacteriocin,




bacteria)





AP01180
Ref, Acidocin
NPKVAHCASQIGRSTAWGAVSGA
2723


J1132 (class IIb




bacteriocin,




bacteria)





AP01181
Ref, Curvaticin
AYPGNGVHCGKYSCTVDKQTAIG
2724


L442 (class IIa
NIGNNAA



bacteriocin,




bacteria)





AP01182
Ref, Bacteriocin 32
FTPSVSFSQNGGVVEAAAQRGYIY
2725


(Bac 32, class IIa
KKYPKGAKVPNKVKMLVNIRGKQ



bacteriocin,
TMRTCYLMSWTASSRTAKYYYYI



bacteria)





AP01183
Ref, Bacteriocin 43
ATYYGNGLYCNKEKCWVDWNQA
2726


(Bac 43,
KGEIGKIIVNGWVNHGPWAPRR



bacteriocin,




bacteria)





AP01184
Ref, Bacteriocin T8
ATYYGNGLYCNKEKCWVDWNQA
2727


(Bac T8, class Ha
KGEIGKIIVNGWVNHGPWAPRR



bacteriocin,




bacteria)





AP01185
Ref, Enterocin B
ENDHRMPNNLNRPNNLSKGGAKC
2728


(EntB, bacteriocin,
GAAIAGGLFGIPKGPLAWAAGLAN



bacteria)
VYSKCN


AP01186
Ref, Acidocin A
KTYYGTNGVHCTKKSLWGKVRLK
2729


(bacteriocin,
NVIPGTLCRKQSLPIKQDLKILLGW



bacteria)
ATGAFGKTFH


AP01187
Ref, Enterocin Q
MNFLKNGIAKWMTGAELQAYKK
2730


(EntQ, class IIc
KYGCLPWEKISC



bacteriocin,




leaderless, i.e. no




signal peptide,




bacteria)





AP01188
Ref, Enterocin
MLAKIKAMIKKFPNPYTLAAKLTT
2731


EJ97 (EntEJ97,
YEINWYKQQYGRYPWERPVA



class IIc




bacteriocin,




leaderless, i.e. no




signal peptide,




bacteria)





AP01189
Ref, Enterocin RJ-
APAGLVAKFGRPIVKKYYKQIIVIQF
2732


11 (EntRJ-11, class
IGEGSAINKIIPWIARMWRT



IIc bacteriocin,




leaderless, i.e. no




signal sequence,




bacteria)





AP01190
Ref, Enterocin L50
MGAIAKLVAKFGWPIVKKYYKQI
2733


(old name:
MQFIGEGWAINKIIEWIKKHI



pediocin L50,




EntL50A, a two-




chain class He




bacteriocin,




leaderless, i.e. no




signal peptide,




bacteria. The




sequence of




EntL50B is




provided in Info)





AP01191
Ref, MR10
MGAIAKLVAKFGWPIVKKYYKQI
2734


(MR10A, class IIc
MQFIGEGWAINKIIDWIKKHI



bacteriocin,




leaderless, i.e. no




signal peptide,




bacteria. For the




sequence of chain




b, see Info)





AP01192
Ref, Halocin S8
SDCNINSNTAADVILCFNQVGSCA
2735


(Hal S8,
LCSPTLVGGPVP



microhalocin,




archaeocins,




archeae)





AP01193
Ref, Halocin C8
DIDITGCSACKYAAGQVCTIGCSA
2736


(HalC8,
AGGFICGLLGITIPVAGLSCLGFVEI



microhalocins,
VCTVADEYSGCGDAVAKEACNRA



archaeocins,
GLC



archaea)





AP01194
Ref, Lacticin 3147
CSTNTFSLSDYWGNNGAWCTLTH
2737


(chain Al, a two-
ECMAWCK



chain lantibiotic,




bacteriocin,




bacteria. The




sequence of chain




A2 is given in Info;




XXD3)





AP01195
Ref, Salivaricin A
KRGSGWIATITDDCPNSVFVCC
2738


(SalA, lantibiotic,




bacteriocin,




bacteria)





AP01196
Ref, Microcin E492
ATYYGNGLYCNKEKCWVDWNQA
2739


(MccE492, class
KGEIGKIIVNGWVNHGPWAPRR



IIb microcins,




bacteriocin,




bacteria; BBM; u-




MccE492,




siderophore




peptide, BBI, XXG)





AP01197
Ref, Hiracin JM79
ATYYGNGLYCNKEKCWVDWNQA
2740


(HirJM79, a Sec-
KGEIGKIIVNGWVNHGPWAPRR



dependent class II




bacteriocin,




bacteria)





AP01198
Ref, Thermophilin
LSCDEGMLAVGGLGAVGGPWGA
2741


9 (BlpDst, class IIb
AVGVLVGAALYCF



bacteriocin,




bacteria. beta-




chains: BlpUst,




BlpEst, BapFst)





AP01199
Ref, Penocin
AKYYGNGVHCGKKTCYVDWGQAT
2742


(PenA, class IIa
ASIGKIIVNGWTQHGPWAHR



bacteriocin,




bacteria)





AP01200
Ref, Salivaricin B
GGGVIQTISHECRMNSWQFLFTCC
2743


(SalB, lantibotic,
S



bacteriocin,




bacteria)





AP01201
Ref, Lacticin 481
KGGSGVIHTISHECNMNSWQFVFT
2744


(lantibiotic, class I




CCS




bacteriocin,




bacteria)





AP01202
Ref, Bacteriocin
KGGSGVIHTISHEVIYNSWNFVFTC
2745


J46 (BacJ46, CS




bacteriocin,




bacteria)





AP01203
Ref, Nukacin A
KKKSGVIPTVSHDCHMNSFQFVFT
2746


(NucA, Nukacin
CCS



ISK-1, NukISK-1,




bacteriocin,




bacteria)





AP01204
Ref, Streptococcin
GKNGVFKTISHECHLNTWAFLATC
2747


A-FF22
CS



(LANTIBIOTIC,




class I bacteriocin,




bacteria)





AP01210
Ref, Jelleine-I
PFKLSLHL
2748


(honeybees, insect,




XXA)





AP01211
Ref, Jelleine -II
TPFKLSLHL
2749


(honeybees, insect,




XXA)





AP01212
Ref, Jelleine -III
EPFKLSLHL
2750


(honeybees, insect,




XXA)





AP01213
Ref,
EFRGSIVIQGTKEGKSRPSLDIDYK
2751



Hymenoptaecin

QRVYDKNGMTGDAYGGLNIRPGQ



(honeybees, insect
PSRQHAGFEFGKEYKNGFIKGQSE



defensin, XXcooh)
VQRGPGGRLSPYFGINGGFRF




AP01216
Ref, Ascaphin -1
GFRDVLKGAAKAFVKTVAGHIAN
2752


(frog, XXA)





AP01218
Ref, Ascaphin -3
GFRDVLKGAAKAFVKTVAGHIANI
2753


(frog)





AP01220
Ref, Ascaphin -5
GIKDWIKGAAKKLIKTVASNIANQ
2754


(frog)





AP01222
Ref, Ascaphin -7
GFKDWIKGAAKKLIKTVASSIANQ
2755


(frog)





AP01223
Ref, Ascaphin-8
GFKDLLKGAAKALVKTVLF
2756


(frog, XXA)





AP01226
Ref, Microcin C7
MRTGNAD
2757


(MccC7, microcin




C51, MccC51,




class I microcins,




bacteriocins,




bacteria. Others:




MccA; XXamp;




BBPe)





AP01227
Ref, Microcin B17
VGIGGGGGGGGGGSCGGQGGGCG
2758


(MccB17, class I
GCSNGCSGGNGGSGGSGSHI



microcins,




bacteriocins, Gram-




negative bacteria;




BBPe)





AP01228
Ref, Microcin V
ASGRDIAMAIGTLSGQFVAGGIGA
2759


(MccV, (old name)
AAGGVAGGAIYDYASTHKPNPAM



Colicin V, ColV;
SPSGLGGTIKQKPEGIPSEAWNYAA



class II microcins,
GRLCNWSPNNLSDVCL



bacteriocins, Gram-




negative bacteria)





AP01229
Ref, Microcin L
GDVNWVDVGKTVATNGAGVIGG
2760


(MccL, class Ha
AFGAGLCGPVCAGAFAVGSSAAV



microcins,
AALYDAAGNSNSAKQKPEGLPPEA



bacteriocins, Gram-
WNYAEGRMCNWSPNNLSDVCL



negative bacteria)





AP01230
Ref, Microcin M
DGNDGQAELIAIGSLAGTFISPGFG
2761


(MccM, class IIb
SIAGAYIGDKVHSWATTATVSPSM



microcins,
SPSGIGLSSQFGSGRGTSSASSSAGS



bacteriocins, Gram-
GS



negative bacteria)





AP01231
Ref, Microcin H47
GGAPATSANAAGAAAIVGALAGIP
2762


(MccH47, class IIb
GGPLGVVVGAVSAGLTTGIGSTVG



microcins,
SGSASSSAGGGS



bacteriocins, Gram-




negative bacteria)





AP 01232
Ref, Microcin 147
MNLNGLPASTNVIDLRGKDMGTYI
2763


(MccI47, class IIb
DANGACWAPDTPSIIMYPGGSGPS



microcins,
YSMSSSTSSANSGS



bacteriocins, Gram-




negative bacteria)









Aibellin
*AcUAUAUAQUFUGUUPVUUEE
2764


[NHC(CH2Ph)HCH2NHCH2CH2]OH




Alamethicin_F-30
*AcUPUAUAQUVUGLUPVUUEQF
2765


OH




Alamethicin_F-50
*AcUPUAUAQUVUGLUPVUUQQF
2766


OH




Alamethicin_II
*AcUPUAUUQUVUGLUPVUUEQF
2767


OH




Ampullosporin
*AcWAUULUQUUUQLUQLOH
2768



Ampullosporin_B
*AcWAUULUQAUUQLUQLOH
2769



Ampullosporin_C
*AcWAUULUQUAUQLUQLOH
2770



Ampullosporin_D
*AcWAUULUQUUAQLUQLOH
2771



Ampullosporin_E1
*AcWAUULUQAUUQLAQLOH
2772



Ampullosporin_E2
*AcWAUULUQUAAQLUQLOH
2773



Ampullosporin_E3
*AcWAUULUQUUAQLAQLOH
2774

Ampullosporin_E4
*AcWAUULUQAAUQLUQLOH
2775



Antiamoebin_I
*AcFUUUJGLUUOQJOUPFOH
2776



Antiamoebin_II
*AcFUUUJGLUUOQJPUPFOH
2777



Antiamoebin_III
*AcFUUUUGLUUOQJOUPFOH
2778



Antiamoebin_IV
*AcFUUUJGLUUOQJOUPFOH
2779



Antiamoebin_V
*AcFUUUJALUUOQJOUPFOH
2780



Antiamoebin_VI
*AcFUUUUGLUUOQUOUPFOH
2781



Antiamoebin_VII
*AcFAUJUGLUUOQJOUPFOH
2782



Antiamoebin_VIII
*AcFUUUJGLUUOQUOUPFOH
2783



Antiamoebin_IX
*AcFUAUJGLUUOQJOUPFOH
2784



Antiamoebin_X
*AcFUUUJGLJUOQUOUPFOH
2785



Antiamoebin_XI
*AcFUUUUALUUOQJOUPFOH
2786



Antiamoebin_XII
*AcFUUUUGLAUOQJOUPFOH
2787



Antiamoebin_XIII
*AcVUUUUGLUUOQJOUPFOH
2788



Antiamoebin_XIV
*AcVUUUVGLUUOQJOUPFOH
2789



Antiamoebin_XV
*AcLUUUUGLUUOQJOUPFOH
2790



Antiamoebin_XVI
*AcLUUUJGLUUOQJOUPFOH
2791



Atroviridin_A
*AcUPUAUAQUVUGLUPVUUQQF
2792


OH




Atroviridin_B
*AcUPUAUAQUVUGLUPVUJQQF
2793


OH




Atroviridin_C
*AcUPUAUUQUVUGLUPVUJQQF
2794


OH




Bergofungin_A
*AcVUUUVGLUUOQJOUFOH
2795



Bergofungin_B
*AcVUUUVGLVUOQUOUFOH
2796



Bergofungin_C
*AcVUUUVGLUUOQUOUFOH
2797



Bergofungin_D
*AcVUUVGLUUOQUOUFOH
2798



Boletusin
*AcFUAUJLQGUUAAUPUUUQW
2799


OH




Cephaibol_A
*AcFUUUUGLJUOQJOUPFOH
2800



Cephaibol_A2
*AcFUUUUALJUOQJOUPFOH
2801



Cephaibol_B
*AcFUUUJGLJUOQJOUPFOH
2802



Cephaibol_C
*AcFUUUUGLJUOQUOUPFOH
2803



Cephaibol_D
*AcFUUUUGLUUOQUOUPFOH
2804



Cephaibol_E
*AcFUUUUGLUUOQJOUPFOH
2805



Cephaibol_P
*AcFJQUITULUOQUOUPFSOH
2806



Cephaibol_Q
*AcFJQUITULUPQUOUPFSOH
2807



Cervinin_1
*AcLUPULUPAUPVLOH
2808



Cervinin_2
*AcLUPULUPAUPVLOCOCH3
2809



Chrysospermin_A
*AcFUSUULQGUUAAUPUUUQW
2810


OH




Chrysospermin_B
*AcFUSUULQGUUAAUPJUUQW
2811


OH




Chrysospermin_C
*AcFUSUJLQGUUAAUPUUUQW
2812


OH




Chrysospermin_D
*AcFUSUJLQGUUAAUPJUUQW
2813


OH




Clonostachin
*AcUOLJOLJOUJUOJI
2814


O[CH(CH(OH)CH2OH)CH(OH)CH(OH)CH2]OH




Emerimicin_II_A
*AcWIQUITULUOQUOUPFOH
2815



Emerimicin_II_B
*AcWIQJITULUOQUOUPFOH
2816



Emerimicin_III
*AcFUUUVGLUUOQJOUFOH
2817



Emerimicin_IV
*AcFUUUVGLUUOQJOAFOH
2818



Harzianin_HB_I
*AcUNLIUPJLUPLOH
2819



Harzianin_HC_I
*AcUNLUPSVUPULUPLOH
2820



Harzianin_HC_III
*AcUNLUPSVUPJLUPLOH
2821



Harzianin_HC_IX
*AcUNLUPAIUPJLUPLOH
2822



Harzianin_HC_VI
*AcUNLUPAVUPULUPLOH
2823



Harzianin_HC_VIII
*AcUNLUPAVUPJLUPLOH
2824



Harzianin_HC_VIII
*AcUNLUPAVUPJLUPLOH
2825



Harzianin_HC_X
*AcUQLUPAVUPJLUPLOH
2826



Harzianin_HC_XI
*AcUNLUPSIUPULUPLOH
2827



Harzianin_HC_XII
*AcUNLUPSIUPJLUPLOH
2828



Harzianin_HC_XIII
*AcUQLUPSIUPJLUPLOH
2829



Harzianin_HC_XIV
*AcUNLUPAIUPULUPLOH
2830



Harzianin_HC_XV
*AcUQLUPAIUPJLUPLOH
2831



Harzianin_HK_VI
*AcUNIIUPLLUPLOH
2832



Harzianin_PCU4
*AcUNLUPSIUPULUPVOH
2833



Helioferin_A
*FaPZZAUIIUUAAE
2834



Helioferin_B
*FaPZZAUIIUUANIAE
2835



Heptaibin
*AcFUUUVGLUUOQUOUFOH
2836



Hypelcin_A
*AcUPUAUUQLUGUUUPVUUQQL
2837


OH




Hypelcin_A_I
*AcUPUAUUQULUGUUPVUUQQL
2838


OH




Hypelcin_A_II
*AcUPUAUAQULUGUUPVUUQQL
2839


OH




Hypelcin_A_III
*AcUPUAUUQULUGUUPVUUQQ
2840


[C7H16NO]




Hypelcin_A_IV
*AcUPUAUUQUIUGUUPVUUQQL
2841


OH




Hypelcin_A-III
*AcUPUAUUQULUGUUPVUJQQL
2842


OH




Hypelcin_A-IX
*AcUPUAUUQUIUGUUPVUJQQL
2843


OH




Hypelcin_A-V
*AcUPUAUUQULUGUUPVUUQQI
2844


OH




Hypelcin_A-VI
*AcUPUAUAQULUGUUPVUUQQI
2845


OH




Hypelcin_A-VII
*AcUPUAUAQULUGUUPVUJQQL
2846


OH




Hypelcin_A-VIII
*AcUPUAUAQUIUGUUPVUUQQL
2847


OH




Hypelcin_B_I
*AcUPUAUUQULUGUUPVUUEQL
2848


OH




Hypelcin_B_II
*AcUPUAUAQULUGUUPVUUEQL
2849


OH




Hypelcin_B_III
*AcUPUAUUQULUGUUPVUJEQL
2850


OH




Hypelcin_B_IV
*AcUPUAUUQUIUGUUPVUUEQL
2851


OH




Hypelcin_B_V
*AcUPUAUUQULUGUUPVUUEQI
2852


OH




Hypomurocin_A_I
*AcUQVVUPLLUPLOH
2853



Hypomurocin_A_II
*AcJQVVUPLLUPLOH
2854



Hypomurocin_A_III
*AcUQVLUPLIUPLOH
2855



Hypomurocin_A_IV
*AcUQIVUPLLUPLOH
2856



Hypomurocin_A_V
*AcUQIIUPLLUPLOH
2857



Hypomurocin_A_Va
*AcUQILUPLIUPLOH
2858



Hypomurocin_B_I
*AcUSALUQUVUGUUPLUUQVOH
2859



Hypomurocin_B_II
*AcUSALUQUVUGUUPLUUQLOH
2860



Hypomurocin_B_Ma
*AcUAALUQUVUGUUPLUUQVOH
2861



Hypomurocin_B_Mb
*AcUSALUQJVUGUUPLUUQVOH
2862



Hypomurocin_B_IV
*AcUSALUQUVUGJUPLUUQVOH
2863



Hypomurocin_B_V
*AcUSALUQUVUGJUPLUUQLOH
2864



Leul_Zervamicin
*AcLIQJITULUOQUOUPFOH
2865



Longibrachin_A_I
*AcUAUAUAQUVUGLUPVUUQQF
2866


OH




Longibrachin_A_II
*AcUAUAUAQUVUGLUPVUJQQF
2867


OH




Longibrachin_A_III
*AcUAUAUUQUVUGLUPVUUQQF
2868


OH




Longibrachin_A_IV
*AcUAUAUUQUVUGLUPVUJQQF
2869


OH


Longibrachin_B_II
*AcUAUAUAQUVUGLUPVUUEQF
2870


OH




Longibrachin_B_III
*AcUAUAUAQUVUGLUPVUJEQF
2871





OH







LP237_F5
*OcUPYUQQUZorQALOH
2872



LP237_F7
*AcUPFUQQUUQALOH
2873



LP237_F8
*OcUPFUQQUZorQALOH
2874



NA_VII
*AcUAAUJQUUUSLUOCH3
2875



Paracelsin_A
*AcUAUAUAQUVUGUUPVUUQQ
2876


FOH




Paracelsin_B
*AcUAUAUAQULUGUUPVUUQQF
2877


OH




Paracelsin_C
*AcUAUAUUQUVUGUUPVUUQQ
2878


FOH




Paracelsin_D
*AcUAUAUUQULUGUUPVUUQQF
2879


OH




Paracelsin_E
*AcUAUAUAQULUGUAPVUUQQF
2880


OH




Peptaibolin
*AcLULUFOH
2881



Peptaivirin_A
*AcFUAUJLQGUUAAUPJUUQW
2882


OH




Peptaivirin_B
*AcFUSUJLQGUUAAUPJUUQFOH
2883



Polysporin_A
*AcUPUAUUQUVUGVUPVUUQQF
2884


OH




Polysporin_B
*AcUPUAUUQUVUGLUPVUUQQF
2885


OH




Polysporin_C
*AcUPUAUUQUIUGLUPVUUQQF
2886


OH




Polysporin_D
*AcUPUAUUQUIUGLUPVUVQQF
2887


OH




Pseudokinin_KLIII
*AcUNIIUPLLUPNH2
2888



Pseudokinin_KLVI
*AcUNIIUPLVhydroxyketopiperazine
2889



Samarosporin_I
*AcFUUUVGLUUOQJOAFOH
2890



Samarosporin_II
*AcFUUUVGLUUOQJOUFOH
2891



Saturnisporin_SA_
*AcUAUAUAQULUGUUPVUUQQF


I
OH
2892



Saturnisporin_SA_
*AcUAUAUAQULUGUUPVUJQQF


II
OH




Saturnisporin_SA_
*AcUAUAUUQULUGUUPVUUQQF
2893

III
OH
2894



Saturnisporin_SA_
*AcUAUAUUQULUGUUPVUJQQF


IV
OH
2895



Stilbellin_I
*AcFUUUVGLUUOQJOAFOH
2896



Stilbellin_II
*AcFUUUVGLUUOQJOUFOH
2897



Stilboflavin_A_1
*AcUPUAUAQUVUGUUPVUUEQV
2898


OH




Stilboflavin_A_2
*AcUPUAUAQULUGUUPVUUEQV
2999


OH




Stilboflavin_A_3
*AcUPUAUUQUVUGUAPVUUEQL
2900


OH




Stilboflavin_A_4
*AcUPUAUAQULUGUUPVUUEQL
2901


OH




Stilboflavin_A_5
*AcUPUAUUQULUGUUPVUUEQV
2902


OH




Stilboflavin_A_6
*AcUPUAUAQULUGUUPVUUEQJ
2903


OH




Stilboflavin_A_7
*AcUPUAUUQULUGUUPVUUEQI
2904


OH




Stilboflavin_B_1
*AcUPUAUAQUVUGUUPVUUQQ
2905


VOH




Stilboflavin_B_2
*AcUPUAUAQULUGUUPVUUQQV
2906


OH




Stilboflavin_B_3
*AcUPUAUAQUVUGUUPVUUQQL
2907


OH




Stilboflavin_B_4
*AcUPUAUAQULUGUUPVUUQQL
2908


OH




Stilboflavin_B_5
*AcUPUAUUQULUGUUPVUUQQV
2909


OH




Stilboflavin_B_6
*AcUPUAUUQUVUGUUPVUUQQ
2910


VOH




Stilboflavin_B_7
*AcUPUAUUQULUGUUPVUUQQL
2911


OH




Stilboflavin_B_8
*AcUPUAUUQUVUGUUPVUUQQL
2912


OH




Stilboflavin_B_9
*AcUPUAUUQULUGUUPVUUQQI
2913


OH




Stilboflavin_B_10
*AcUPUAUUQUVUGUUPVUUQQI
2914


OH




Suzukacillin
*AcUAUAUAQUUUGLUPVUUQQF
2915


OH




Trichobrachin_A-I
*AcUNLLUPLUUPLOH
2916



Trichobrachin_A-II
*AcUNLLUPVLUPVOH
2917



Trichobrachin_A-III
*AcUNVLUPLLUPVOH
2918



Trichobrachin_A-IV
*AcUNLVUPLLUPVOH
2919



Trichobrachin_B-I
*AcUNLLUPVUVPLOH
2920



Trichobrachin_B-I_
*AcUNVLUPLUVPLOH
2921



Trichobrachin_B-III
*AcUNLVUPLUVPLOH
2922



Trichobrachin_B-IV
*AcUNLLUPLUVPVOH
2923



Trichocellin_TC-A-I
*AcUAUAUAQULUGUUPVUUQQF
2924


OH




Trichocellin_TC-A-
*AcUAUAUAQULUGUUPVUJQQF
2925

II
OH




Trichocellin_TC-A-
*AcUAUAUAQUIUGUUPVUUQQF
2926

III
OH




Trichocellin_TC-A-
*AcUAUAUAQUIUGUUPVUJQQF
2927

IV
OH




Trichocellin_TC-A-V
*AcUAUAUAQULUGLUPVUUQQF
2928


OH




Trichocellin_TC-A-
*AcUAUAUAQULUGLUPVUJQQF
2929

VI
OH




Trichocellin_TC-A-
*AcUAUAUAQUIUGLUPVUUQQF
2930

VII
OH




Trichocellin_TC-A-
*AcUAUAUAQUIUGLUPVUJQQF
2931

VIII
OH




Trichocellin_TC-B-I
*AcUAUAUAQULUGUUPVUUEQF
2932


OH




Trichocellin_TC-B-II
*AcUAUAUAQULUGUUPVUJEQF
2933


OH




Trichodecenin_TD_I
*(Z)-4-decenoylGGLUGILOH
2934



Trichodecenin_TD_II
*(Z)-4-decenoylGGLUGLLOH
2935



Trichogin
AIV*OcUGLUGGLUGILOH
2936



Trichokindin_Ia
*AcUSAUUQJLUAUUPLUUQIOH
2937



Trichokindin_Ib
*AcUSAUJQULUAUUPLUUQIOH
2938



Trichokindin_IIa
*AcUSAUUQULUAJUPLUUQIOH
2939



Trichokindin_IIb
*AcUSAUJQJLUAUUPLUUQLOH
2940



Trichokindin_Ma
*AcUSAUUQJLUAJUPLUUQLOH
2941



Trichokindin_Mb
*AcUSAUJQULUAJUPLUUQLOH
2942



Trichokindin_IV
*AcUSAUJQJLUAUUPLUUQIOH
2943



Trichokindin_Va
*AcUSAUUQJLUAJUPLUUQIOH
2944



Trichokindin_Vb
*AcUSAUJQULUAJUPLUUQIOH
2945



Trichokindin_VI
*AcUSAUJQJLUAJUPLUUQLOH
2946



Trichokindin_VII
*AcUSAUJQJLUAJUPLUUQIOH
2947



Trichokoninb_Ia
*AcUAUAUAQUVUGLAPVUUQQF
2948


OH




Trichokonin_Ib
*AcUGUAUAQUVUGLUPVUUQQF
2949


OH




Trichokonin_IIa
*AcUAUAUAQUVUGLUPAUUQQF
2950


OH




Trichokonin_IIb
*AcAAUAUAQUVUGLUPVUUQQF
2951


OH




Trichokonin_IIc
*AcUAAAUAQUVUGLUPVUUQQF
2952


OH




Trichokonin_V
*AcUAUAUQUVUGLUPVUUQQF
2953


OH




Trichokonin_VII
*AcUAUAUAQUVUGLUPVUJQQF
2954


OH




Trichokonin_VIII
*AcUAUAUUQUVUGLUPVUUQQF
2955


OH




Trichokonin_IX
*AcUAUAUAQUVUGLUPVUJQQF
2956


OH




Tricholongin_BI
*AcUGFUUQUUUSLUPVUUQQL
2957


OH




Tricholongin_BII
*AcUGFUUQUUUSLUPVUJQQL
2958


OH




Trichopolyn_I
*FaPZZAUUIAUUANIAE
2959



Trichopolyn_II
*FaPZZAUUVAUUANIAE
2960



Trichopolyn_III
*FaPZZAUUIAUAANIAE
2961



Trichopolyn_IV
*FaPZZAUUVAUAANIAE
2962



Trichopolyn_V
*Fa′PZZAUUIAUUAN/JAB
2963



Trichorovin_TV_Ia
*AcUNVLxUPLxLxUPVOH
2964



Trichorovin_TV_Ib
*AcUNVVUPLxLxUPLxOH
2965



Trichorovin_TV_IIa
*AcUNVVUPLxLxUPLxOH
2966



Trichorovin_TV_IIb
*AcUNLxVUPLxLxUPVOH
2967



Trichorovin_TV_IIIa
*AcUQVVUPLxLxUPLxOH
2968



Trichorovin_TV_IIIb
*AcUQVLxUPLxLxUPVOH
2969



Trichorovin_TV_IVa
*AcUQVVUPLxLxUPLxOH
2970



Trichorovin_TV_IVb
*AcUQLxVUPLxLxUPVOH
2971



Trichorovin_TV_IVc
*AcUNVLxUPLxLxUPLxOH
2972



Trichorovin_TV_IXa
*AcUQVLxUPLxLxUPLxOH
2973



Trichorovin_TV_IXb
*AcUQLxLxUPLxLxUPVOH
2974



Trichorovin_TV_Va
*AcUNVLxUPLxLxUPLxOH
2975



Trichorovin_TV_Vb
*AcUNLxLxUPLxLxUPVOH
2976



Trichorovin_TV_VIa
*AcUNVLxUPLxLxUPLxOH
2977



Trichorovin_TV_VIb
*AcUNLxLxUPLxLxUPVOH
2978



Trichorovin_TV_VIIa
*AcUNLxVUPLxLxUPLxOH
2979



Trichorovin_TV_VIIb
*AcUQVLxUPLxLxUPVOH
2980



Trichorovin_TV_VIII
*AcUQVLxUPLxLxUPLxOH
2981



Trichorovin_TV_Xa
*AcUQLxVUPLxLxUPLxOH
2982



Trichorovin_TV_Xb
*AcUNLxLxUPLxLxUPLxOH
2983



Trichorovin_TV_XIIa
*AcUNIIUPLLUPIOH
2984



Trichorovin_TV_XIIb
*AcUNLxLxUPLxLxUPLOH
2985



Trichorovin_TV_XIII
*AcUQLxLxUPLxLxUPLxOH
2986



Trichorovin_TV_XIV
*AcUQLxLxUPLxLxUPLxOH
2987



Trichorozin_I
*AcUNILUPILUPVOH
2988



Trichorozin_II
*AcUQILUPILUPVOH
2989



Trichorozin_III
*AcUNILUPILUPLOH
2990



Trichorozin_IV
*AcUOILUPILUPLOH
2991



Trichorzianine_TA_I
*AcUAAUUQUUUSLUPVUIQQW
2992

IIc
OH




Trichorzianine_TB_
*AcUAAUUQUUUSLUPLUIQEW
2993

IIa
OH




Trichorzianine_TB_
*AcUAAUUQUUUSLUPVUIQEW
2994

IIIc
OH




Trichorzianine_TB_
*AcUAAUJQUUUSLUPVUIQEW
2995

IVb
OH




Trichorzianine_TB_
*AcUAAUUQUUUSLUPLUIQEFOH
2996

Vb





Trichorzianine_TB_
*AcUAAUJQUUUSLUPLUIQEFOH
2997

VIa





Trichorzianine_TB_
*AcUAAUUQUUUSLUPVUIQEF
2998

VIb
OH




Trichorzianine_TB_
*AcUAAUJQUUUSLUPVUIQEFOH
2999

VII





Trichorzin_HA_I
*AcUGAUUQUVUGLUPLUUQLOH
3000



Trichorzin_HA_II
*AcUGAUUQUVUGLUPLUJQLOH
3001



Trichorzin_HA_III
*AcUGAUJQUVUGLUPLUUQLOH
3002



Trichorzin_HA_V
*AcUGAUJQUVUGLUPLUJQLOH
3003



Trichorzin_HA_VI
*AcUGAUJQJVUGLUPLUJQLOH
3004



Trichorzin_HA_VII
*AcUGAUJQVVUGLUPLUJQLOH
3005



Trichorzin_MA_I
*AcUSAUUQULUGLUPLUUQVOH
3006



Trichorzin_MA_II
*AcUSAUJQULUGLUPLUUQVOH
3007



Trichorzin_MA_III
*AcUSAUJQJLUGLUPLUUQVOH
3008



Trichorzin_PA_II
*AcUSAUJQUVUGLUPLUUQWOH
3009



Trichorzin_PA_IV
*AcUSAUJQJVUGLUPLUUQWOH
3010



Trichorzin_PA_V
*AcUSAJJQUVUGLUPLUUQWOH
3011



Trichorzin_PA_VI
*AcUSAUJQUVUGLUPLUUQFOH
3012



Trichorzin_PA_VII
*AcUSAJJQUVUGLUPLUUQWOH
3013



Trichorzin_PA_VIII
*AcUSAUJQJVUGLUPLUUQFOH
3014



Trichorzin_PA_IX
*AcUSAJJQUVUGLUPLUUQFOH
3015



Trichorzin_PAU4
*AcUSAUUQUVUGLUPLUUQWOH
3016



Trichosporin_TS-B-
*AcUAGUAUQULxAAVxAPVUVxQ
3017

1a-1
QFOH




Trichosporin_TS-B-
*AcUAGAUUQULxAAVxAPVUVxQ
3018

1a-2
QFOH




Trichosporin_TS-B-
*AcUAGAUUQULxUGLxAPVUAQ
3019

1b
QFOH




Trichosporin_TS-B-
*AcUASAUUQULxUGLxAPVUUQQ
3020

1d
FOH




Trichosporin_TS-B-
*AcUAGAUUQULxUGLxUPVUUQ
3021

1e
QFOH




Trichosporin_TS-B-
*AcUASAUUQULxUGLxUPVUUQQ
3022

1f
FOH




Trichosporin_TS-B-
*AcUAGAUUQULxUGLxAPVUUQ
3023

1g
QFOH




Trichosporin_TS-B-
*AcUAGAUUQULxUGLxUPVUVxQ
3024

1h
QFOH




Trichosporin_TS-B-Ia
*AcUASAUUQULUGLUPVUUQQF
3025


OH


Trichosporin_TS-B-
*AcUAAAUUQULUGLUPVUUQQF
3026

IIIa
OH




Trichosporin_TS-B-
*AcUAAAUUQUIUGLUPVUAQQF
3027

IIIb
OH




Trichosporin_TS-B-
*AcUAAAAUQUIUGLUPVUUQQF
3028

IIIc
OH




Trichosporin_TS-B-
*AcUAAAUUQUVUGLUPVUUQQF
3029

IIId
OH




Trichosporin_TS-B-
*AcUAAAUUQULUGLUPVUJQQF
3030

IVb
OH




Trichosporin_TS-B-
*AcUAUAUUQUVUGLUPVUUQQF
3031

IVc
OH




Trichosporin_TS-B-
*AcUAAAUUQUVUGLUPVUJQQF
3032

IVd
OH




Trichosporin_TS-B-
*AcUAAAUUQUIUGLUPVUUQQF
3033

V
OH




Trichosporin_TS-B-
*AcUAUAUUQUIUGLUPVUUQQF
3034

VIa
OH




Trichosporin_TS-B-
*AcUAAAUUQUIUGLUPVUJQQF
3035

VIb
OH




Trichotoxin_A-40
*AcUGULUEUUUAUUPLUJQVOH
3036



Trichotoxin_A-40_I
*AcUGULUQUUAAUUPLUUEVOH
3037



Trichotoxin_A-40_II
*AcUGULUQUUUAAUPLUUEVOH
3038



Trichotoxin_A-40_III
*AcUGULUQUUAAUUPLUJEVOH
3039



Trichotoxin_A-40_IV
*AcUGULUQUUUAUUPLUUEVOH
3040



Trichotoxin_A-40_V
*AcUGULUQUUUAUUPLUJEVOH
3041



Trichotoxin_A-40_Va
*AcUAULUQUUUAUUPLUUEVOH
3042



Trichotoxin_A-50_E
*AcUGULUQUUUAAUPLUUQVOH
3043



Trichotoxin_A-50_F
*AcUGULUQUUAAAUPLUJQVOH
3044



Trichotoxin_A-50_G
*AcUGULUQUUUAAUPLUJQVOH
3045



Trichotoxin_A-50_H
*AcUAULUQUUUAAUPLUJQVOH
3046



Trichotoxin_A-50_I
*AcUGULUQUUUAUUPLUJQVOH
3047



Trichotoxin_A-50_J
*AcUAULUQUUUAUUPLUJQVOH
3048



Trichovirin-1a
*AcUGALAQVxVUGUUPLUUQL
3049


OH


Trichovirin-Ib
*AcUGALUQAVUGJUPLUUQLOH
3050



Trichovirin-IIa
*AcUGALAQUVUGJUPLUUQLOH
3051



Trichovirin-lIb
*AcUGALUQUVUGUUPLUUQLOH
3052



Trichovirin-IIc
*AcUGALUQVxVUGUUPLUUQL
3053


OH




Trichovirin-IIIa
*AcUGALUQJVUGUUPLUUQLOH
3054



Trichovirin-IIb
*AcUGALJQJUUGUUPLUUQLOH
3055



Trichovirin-IVa
*AcUGALJQJVUGUUPLUUQLOH
3056



Trichovirin-IVb
*AcUGALUQUVUGJUPLUUQLOH
3057



Trichovirin-V
*AcUGALUQJVUGJUPLUUQLOH
3058



Trichovirin-VIa
*AcUGALUQJLUGJUPLUUQLOH
3059



Trichovirin-VIb
*AcUGALJQJVUGJUPLUUQLOH
3060



Trikoningin_KA_V
*AcUGAUIQUUUSLUPVUIQQLOH
3061



Trikoningin_KB_I
*OcUGVUGGVUGILOH
3062



Trikoningin_KB_II
*OcJGVUGGVUGILOH
3063



Tylopeptin_A
*AcWVUJAQAUSUALUQLOH
3064



Tylopeptin_B
*AcWVUUAQAUSUALUQLOH
3065



XR586
*AcWJQUITULUPQUOJPFGOH
3066



Zervamicin_A-1-16
*B0cWIAUIVULUPAUPUPFOCH3
3067



Zervamicin_ZIA
*AcWIEJVTULUOQUOUPFOH
3068



Zervamicin_ZIB
*AcWVEJITULUOQUOUPFOH
3069



Zervamicin_ZIB′
*AcWIEUITULUOQUOUPFOH
3070



Zervamicin_ZIC
*AcWIEJITULUOQUOUPFOH
3071



Zervamicin_ZII-1
*AcWIQUVTULUOQUOUPFOH
3072



Zervamicin_ZII-2
*AcWIQUITUVUOQUOUPFOH
3073



Zervamicin_ZII-3
*AcWVQUITULUOQUOUPFOH
3074



Zervamicin_ZII-4
*AcWIQJVTULUOQUOUPFOH
3075



Zervamicin_ZII-5
*AcWIQJITUVUOQUOUPFOH
3076



Zervamicin_ZIIA
*AcWIQUITULUOQUOUPFOH
3077



Zervamicin_ZIIB
*AcWIQJITULUOQUOUPFOH
3078



CAMEL135
GWRLIKKILRVFKGL
3079

(CAM135)





Novispirin G2
KNLRIIRKGIHIIKKY*
3080



B-33
FKKFWKWFRRF
3081



B-34
LKRFLKWFKRF
3082



B-35
KLFKRWKHLFR
3083



B-36
RLLKRFKHLFK
3084



B-37
FKTFLKWLHRF
3085



B-38
IKQLLHFFQRF
3086



B-39
KLLQTFKQIFR
3087



B-40
RILKELKNLFK
3088



B-41
LKQFVHFIHRF
3089



B-42
VKTLLHIFQRF
3090



B-43
KLVEQLKEIFR
3091



B-44
RVLQEIKQILK
3092



B-45
VKNLAELVHRF
3093



B-46
ATHLLHALQRF
3094



B-47
KLAENVKEILR
3095



B-48
RALHEAKEALK
3096



B-49
FHYFWHWFHRF
3097



B-50
LYHFLHWFQRF
3098



B-51
YLFQTWQHLFR
3099



B-52
YLLTEFQHLFK
3100



B-53
FKTFLQWLHRF
3101



B-54
IKTLLHFFQRF
3102



B-55
KLLQTFNQIFR
3103



B-56
TILQSLKNIFK
3104



B-57
LKQFVKFIHRF
3105



B-58
VKQLLKIFNRF
3106



B-59
KLVQQLKNIFR
3107



B-60
RVLNQVKQILK
3108



B-61
VKKLAKLVRRF
3109



B-62
AKRLLKVLKRF
3110



B-63
KLAQKVKRVLR
3111



B-64
RALKRIKHVLK
3112



1C-1
RRRRWWW
3113



1C-2
RRWWRRW
3114



1C-3
RRRWWWR
3115



1C-4
RWRWRWR
3116



2C-1
RRRFWWR
3117



2C-2
RRWWRRF*
3118



2C-3
RRRWWWF*
3119



2C-4
RWRWRWF*
3120



3C-1
RRRRWWK
3121



3C-2
RRWWRRK
3122



3C-3
RRRWWWK
3123



3C-4
RWRWRWK
3124



4C-1
RRRKWWK
3125



4C-2
RRWKRRK
3126



4C-3
RRRKWWK
3127



4C-4
RWRKRWK
3128



a-3
LHLLHQLLHLLHQF*
3129



a-4
AQAAHQAAHAAHQF*
3130



a-5
KLKKLLKKLKKLLK
3131



a-6
LKLLKKLLKLLKKF*
3132



a-7
LQLLKQLLKLLKQF*
3133



a-8
AQAAKQAAKAAKQF*
3134



a-9
RWRRWWRHFHHFFH*
3135



a-10
KLKKLLKRWRRWWR
3136



a-11
RWRRLLKKLHHLLH*
3137



a-12
KLKKLLKHLHHLLH*
3138



BD-1
FVF RHK WVW KHR FLF
3139



BD-2
VFI HRH VWV HKH VLF
3140



BD-3
WR WR ARWR WR LR WR F
3141



BD-4
WR IH LR AR LH VK FR F
3142



BD-5
LR IH AR FK VH IR LK F
3143



BD-6
FH IK FR VH LK VR FH F
3144



BD-7
FH VK IH FR LH VK FH F
3145



BD-8
LH IH AH FH VH IH LH F
3146



BD-9
FK IHFRLK VHIRFK F
3147



BD-10
FK AH IR FK LR VK FH F
3148



BD-11
LK AK IK FK VK LK IK F
3149



BD-12
WIW KHK FL HRH FLF
3150



BD-13
VFL HRH VI KHK LVF
3151



BD-14
FL HKH VL RHR IVF
3152



BD-15
VF KHK IV HRH ILF
3153



BD-16
FLF KH LFL HR IFF
3154



BD-17
LF KH ILI HR VIF
3155



BD-18
FL HKH LF KHK LF
3156



BD-19
VF RHR FI HRH VF
3157



BD-20
FI HK LV HKH VLF
3158



BD-21
VL RH LF RHR IVF
3159



BD-22
LV HK LIL RH LLF
3160



BD-23
VF KR VLI HK LIF
3161



BD-24
IV RK FLF RHK VF
3162



BD-25
VL KH VIA HKR LF
3163



BD-26
FI RK FLF KH LF
3164



BD-27
VI RH VWV RK LF
3165



BD-28
FLF RHR F RHR LVF
3166



BD-29
LFL HKH A KHK FLF
3167



BD-30
F KHK F KHK FIF
3168



BD-31
L RHR L RHR LIF
3169



BD-32
LIL K FLF K FVF
3170



BD-33
VLI R ILV R VIF
3171



BD-34
F RHR F RHR F
3172



BD-35
L KHK L KHK F
3173



BD-36
F K F KHK LIF
3174



BD-37
L R L RHR VLF
3175



BD-38
F K FLF K FLF
3176



BD-39
L R LFL R WLF
3177



BD-40
F K FLF KHK F
3178



BD-41
L R LFL RHR F
3179



BD-42
FKFLFKF
3180



BD-43
LRLFLRF
3181



AA-1
HHFFHHFHHFFHHF*
3182



AA-2
FHFFHEIFFHFFHHF*
3183



AA-3
KLLK-GAT-FHFFHHFFHFFHHF
3184



AA-4
KLLK-FHFFHHFFHFFHHF
3185



AA-5
FHFFHHFFHFFHHFKLLK
3186



RIP
YSPWTNF*
3187



Lariatin A
c(Gly-Ser-Gln-Leu-Val-Tyr-Arg-Glu)-Trp-
3188

(anti-mycobacteria)
Val-Gly-His-Ser-Asn-Val-Ile-Lys-Pro




Lariatin B
c(Gly-Ser-Gln-Leu-Val-Tyr-Arg-Glu)-Trp-
3189

(anti-mycobacteria)
Val-Gly-His-Ser-Asn-Val-Ile-Lys-Gly-



Pro-Pro



Abreviations:

U-Aminoisobutyric Acid (Aib);

J-Isovaline (Iva);

O-Hydroxyproline (Hyp);

Z-Ethylnorvaline (EtNor);

x or xx means L or I at that position;

Ac-optionally acetylated N-term;

OH, OCH3-optional C-term;

Alkane long chains are noted in brackets;

*optionally amidated C-terminus. Where protecting groups are shown, the gropus are optional. Conversely any of the peptides shown without protecting groups can, optionally one or more protecting groups. Where peptides are shown circularized, linear forms bear are also contemplated. Conversely, where linear peptides are shown circularlized versions are also contemplated.


















































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































In certain embodiments the antimicrobial peptide consists of or comprises the amino acid sequence of LL-37 (LLGDFFRK SKEKIGKEFKRIVQRIKD FLRNL VPRTES, SEQ ID NO:3190) or a variant of LL-37. LL-37 is a cathelicidin anti-microbial corresponding to amino acids 134-170 of the human cationic antimicrobial protein 18 (hCAP18). In certain embodiments the antimicrobial peptide consists of or comprises the amino acid sequence of an LL-37 variant as described in U.S. Patent Publication No: 2009/0156499 A1). Illustrative variants comprise or consist of the amino acid sequence having at least 90%, 95%, or 98% sequence identity with the amino acid sequence FKRIVQRIKDFLRX 1 (SEQ ID NO:3191), where X 1 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8 amino acids. In certain embodiments illustrative variants comprise or consist of the amino acid sequence having at least 90%, 95%, or 98% sequence identity with the amino acid sequence X 1 RLFDKIRQVIRKFX 2 (SEQ ID NO:3192) where X 1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8 amino acids and X 2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 amino acids.
In certain embodiments the antimicrobial peptide consists of or comprises the amino acid sequence of an LL-37 variant shown in Table 15.





TABLE 15



LL-37 peptide and variants.







SEQ



ID

ID
Amino acid sequence
NO



LL-37
LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNL
3193


VPRTES




Cys-LL -37
CLLGDFFRKSKEKIGKEFKRIVQRIKDFLRN
3194


LVPRTES




LL-37(17-32)

FKRIVQRIKDFLRNLV

3195



Cys-LL-37-
CLLGDFFRKSKEKIGKEFKRIVQRIKDFLRN
3196

Cys
LVPRTESC




LL-37FK-13
FKRIVQRIKDFLR
3197



LL-37FKR
FKRIVQRIKDFLRNLVPRTES
3198



LL-37GKE
GKEFKRIVQRIKDFLRNLVPR
3199



LL-37KRI
KRIVQRIKDFLRNLVPRTES
3200



LL-37LLG
LLGDFFRKSKEKIGKEFKRIV
3201



LL-37RKS
RKSKEKIGKEFKRIVQRIKDFLRNLVPRTES
3202



LL-37SKE
SKEKIGKEFKRIVQRIKDFLR
3203



LL-37-Cys
LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNL
3204


VPRTESC

















































A number of antimicrobial peptides are also disclosed in U.S. Pat. Nos. 7,271,239, 7,223,840, 7,176,276, 6,809,181, 6,699,689, 6,420,116, 6,358,921, 6,316,594, 6,235,973, 6,183,992, 6,143,498, 6,042,848, 6,040,291, 5,936,063, 5,830,993, 5,428,016, 5,424,396, 5,032,574, 4,623,733, which are incorporated herein by reference for the disclosure of particular antimicrobial peptides.
v. Ligands.
In certain embodiments the effector can comprise one ore more ligands, epitope tags, and/or antibodies. In certain embodiments preferred ligands and antibodies include those that bind to surface markers on immune cells. Chimeric moieties utilizing such antibodies as effector molecules act as bifunctional linkers establishing an association between the immune cells bearing binding partner for the ligand or antibody and the target microorganism(s).
The terms “epitope tag” or “affinity tag” are used interchangeably herein, and used refers to a molecule or domain of a molecule that is specifically recognized by an antibody or other binding partner. The term also refers to the binding partner complex as well. Thus, for example, biotin or a biotin/avidin complex are both regarded as an affinity tag. In addition to epitopes recognized in epitope/antibody interactions, affinity tags also comprise “epitopes” recognized by other binding molecules (e.g. ligands bound by receptors), ligands bound by other ligands to form heterodimers or homodimers, His 6 bound by Ni-NTA, biotin bound by avidin, streptavidin, or anti-biotin antibodies, and the like.
Epitope tags are well known to those of skill in the art. Moreover, antibodies specific to a wide variety of epitope tags are commercially available. These include but are not limited to antibodies against the DYKDDDDK (SEQ ID NO:3205) epitope, c-myc antibodies (available from Sigma, St. Louis), the HNK-1 carbohydrate epitope, the HA epitope, the HSV epitope, the His 4 (SEQ ID NO:3206), His 5 (SEQ ID NO:3207), and His 6 (SEQ ID NO:3208) epitopes that are recognized by the His epitope specific antibodies (see, e.g., Qiagen), and the like. In addition, vectors for epitope tagging proteins are commercially available. Thus, for example, the pCMV-Tag1 vector is an epitope tagging vector designed for gene expression in mammalian cells. A target gene inserted into the pCMV-Tag1 vector can be tagged with the FLAG® epitope (N-terminal, C-terminal or internal tagging), the c-myc epitope (C-terminal) or both the FLAG (N-terminal) and c-myc (C-terminal) epitopes.
vi. Lipids and Liposomes.
In certain embodiments the effectors comprise one or more microparticles or nanoparticles that can be loaded with an effector agent (e.g., a pharmaceutical, a label, etc.). In certain embodiments the microparticles or nanoparticles are lipidic particles. Lipidic particles are microparticles or nanoparticles that include at least one lipid component forming a condensed lipid phase. Typically, a lipidic nanoparticle has preponderance of lipids in its composition. Various condensed lipid phases include solid amorphous or true crystalline phases; isomorphic liquid phases (droplets); and various hydrated mesomorphic oriented lipid phases such as liquid crystalline and pseudocrystalline bilayer phases (L-alpha, L-beta, P-beta, Lc), interdigitated bilayer phases, and nonlamellar phases (see, e.g., The Structure of Biological Membranes, ed. by P. Yeagle, CRC Press, Bora Raton, Fla., 1991). Lipidic microparticles include, but are not limited to a liposome, a lipid-nucleic acid complex, a lipid-drug complex, a lipid-label complex, a solid lipid particle, a microemulsion droplet, and the like. Methods of making and using these types of lipidic microparticles and nanoparticles, as well as attachment of affinity moieties, e.g., antibodies, to them are known in the art (see, e.g., U.S. Pat. Nos. 5,077,057; 5,100,591; 5,616,334; 6,406,713; 5,576,016; 6,248,363; Bondi et al. (2003) Drug Delivery 10: 245-250; Pedersen et al., (2006) Eur. J. Pharm. Biopharm. 62: 155-162, 2006 (solid lipid particles); U.S. Pat. Nos. 5,534,502; 6,720,001; Shiokawa et al. (2005) Clin. Cancer Res. 11: 2018-2025 (microemulsions); U.S. Pat. No. 6,071,533 (lipid-nucleic acid complexes), and the like).
A liposome is generally defined as a particle comprising one or more lipid bilayers enclosing an interior, typically an aqueous interior. Thus, a liposome is often a vesicle formed by a bilayer lipid membrane. There are many methods for the preparation of liposomes. Some of them are used to prepare small vesicles (d<0.05 micrometer), some for larger vesicles (d>0.05 micrometer). Some are used to prepare multilamellar vesicles, some for unilamellar ones. Methods for liposome preparation are exhaustively described in several review articles such as Szoka and Papahadjopoulos (1980) Ann. Rev. Biophys. Bioeng., 9: 467, Deamer and Uster (1983) Pp. 27-51 In: Liposomes, ed. M. J. Ostro, Marcel Dekker, New York, and the like.
In various embodiments the liposomes include a surface coating of a hydrophilic polymer chain. “Surface-coating” refers to the coating of any hydrophilic polymer on the surface of liposomes. The hydrophilic polymer is included in the liposome by including in the liposome composition one or more vesicle-forming lipids derivatized with a hydrophilic polymer chain. In certain embodiments, vesicle-forming lipids with diacyl chains, such as phospholipids, are preferred. One illustrative phospholipid is phosphatidylethanolamine (PE), which contains a reactive amino group convenient for coupling to the activated polymers. One illustrative PE is distearoyl PE (DSPE). Another example is non-phospholipid double chain amphiphilic lipids, such as diacyl- or dialkylglycerols, derivatized with a hydrophilic polymer chain.
In certain embodiments a hydrophilic polymer for use in coupling to a vesicle forming lipid is polyethyleneglycol (PEG), preferably as a PEG chain having a molecular weight between 1,000-10,000 Daltons, more preferably between 1,000-5,000 Daltons, most preferably between 2,000-5,000 Daltons. Methoxy or ethoxy-capped analogues of PEG are also useful hydrophilic polymers, commercially available in a variety of polymer sizes, e.g., 120-20,000 Daltons.
Other hydrophilic polymers that can be suitable include, but are not limited to polylactic acid, polyglycolic acid, polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses, such as hydroxymethylcellulose or hydroxyethylcellulose.
Preparation of lipid-polymer conjugates containing these polymers attached to a suitable lipid, such as PE, have been described.
The liposomes can, optionally be prepared for attachment to one or more targeting moieties described herein. Here the lipid component included in the liposomes would include either a lipid derivatized with the targeting moiety, or a lipid having a polar-head chemical group, e.g., on a linker, that can be derivatized with the targeting moiety in preformed liposomes, according to known methods.
Methods of functionalizing lipids and liposomes with affinity moieties such as antibodies are well known to those of skill in the art (see, e.g., DE 3,218,121; Epstein et al. (1985) Proc. Natl. Acad. Sci., USA, 82:3688 (1985); Hwang et al. (1980) Proc. Natl. Acad. Sci., USA, 77: 4030; EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese patent application 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324, all of which are incorporated herein by reference).
vii. Agents that Physically Disrupt the Extracellular Matrix within a Community of Microorganisms
In certain embodiments, peptides can be coupled to agents that physically disrupt the extracellular matrix within a community of microorganisms, for example a biofilm. In certain preferred embodiments, such an agent could be a bacterial cell-wall degrading enzyme, for example SAL-2, or any species of glycosidase, alginase, peptidase, proteinase, lipase, or DNA or RNA degrading enzyme or compound, for example rhRNase. Disruption of extracellular matrix of biofilms can result in clearance and therapeutic benefit.
Peptides can also be attached to antimicrobial proteins, such as Protein Inhibitor C or Colicin, or fragments thereof, for example the IIa domain of Colicin, or the heparin-binding domain of Protein Inhibitor C.
viii. Polymeric Microparticles and/or Nanoparticles.
In certain embodiments the effector(s) comprise polymeric microparticles and/or nanoparticles and/or micelles.
Microparticle and nanoparticle-based drug delivery systems have considerable potential for treatment of various microorganisms. Technological advantages of polymeric microparticles or nanoparticles used as drug carriers are high stability, high carrier capacity, feasibility of incorporation of both hydrophilic and hydrophobic substances, and feasibility of variable routes of administration, including oral application and inhalation. Polymeric nanoparticles can also be designed to allow controlled (sustained) drug release from the matrix. These properties of nanoparticles enable improvement of drug bioavailability and reduction of the dosing frequency.
Polymeric nanoparticles are typically micron or submicron (<1 μm) colloidal particles. This definition includes monolithic nanoparticles (nanospheres) in which the drug is adsorbed, dissolved, or dispersed throughout the matrix and nanocapsules in which the drug is confined to an aqueous or oily core surrounded by a shell-like wall. Alternatively, in certain embodiments, the drug can be covalently attached to the surface or into the matrix.
Polymeric microparticles and nanoparticles are typically made from biocompatible and biodegradable materials such as polymers, either natural (e.g., gelatin, albumin) or synthetic (e.g., polylactides, polyalkylcyanoacrylates), or solid lipids. In the body, the drug loaded in nanoparticles is usually released from the matrix by diffusion, swelling, erosion, or degradation. One commonly used material is poly(lactide-co-glycolide) (PLG).
Methods of fabricating and loading polymeric nanoparticles or microparticles are well known to those of skill in the art. Thus, for example, Matsumoto et al. (1999) Intl. J. Pharmaceutics, 185: 93-101 teaches the fabrication of poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) nanoparticles, Chawla et al. (2002) Intl. J. Pharmaceutics 249: 127-138, teaches the fabrication and use of poly(e-caprolactone) nanoparticles delivery of tamifoxen, and Bodmeier et al. (1988) Intl. J. Pharmaceutics, 43: 179-186, teaches the preparation of poly(D,L-lactide) microspheres using a solvent evaporation method. “Intl. J. Pharmaceutics, 1988, 43, 179-186. Other nanoparticle formulations are described, for example, by Williams et al. (2003) J. Controlled Release, 91: 167-172; Leroux et al. (1996) J. Controlled Release, 39: 339-350; Soppimath et al. (2001) J. Controlled Release, 70: 1-20; Brannon-Peppas (1995) Intl. J. Pharmaceutics, 116: 1-9; and the like.
C) Peptide Preparation.
The peptides described herein can be chemically synthesized using standard chemical peptide synthesis techniques or, particularly where the peptide does not comprise “D” amino acid residues, the peptide can be recombinantly expressed. Where the “D” polypeptides are recombinantly expressed, a host organism (e.g. bacteria, plant, fungal cells, etc.) can be cultured in an environment where one or more of the amino acids is provided to the organism exclusively in a D form. Recombinantly expressed peptides in such a system then incorporate those D amino acids.
In certain embodiments, D amino acids can be incorporated in recombinantly expressed peptides using modified amino acyl-tRNA synthetases that recognize D-amino acids.
In certain embodiments the peptides are chemically synthesized by any of a number of fluid or solid phase peptide synthesis techniques known to those of skill in the art. Solid phase synthesis in which the C-terminal amino acid of the sequence is attached to an insoluble support followed by sequential addition of the remaining amino acids in the sequence is a preferred method for the chemical synthesis of the polypeptides of this invention. Techniques for solid phase synthesis are well known to those of skill in the art and are described, for example, by Barany and Merrifield (1963) Solid - Phase Peptide Synthesis ; pp. 3-284 in The Peptides: Analysis, Synthesis, Biology. Vol. 2 : Special Methods in Peptide Synthesis, Part A .; Merrifield et al. (1963) J. Am. Chem. Soc., 85: 2149-2156, and Stewart et al. (1984) Solid Phase Peptide Synthesis, 2nd ed. Pierce Chem. Co., Rockford, Ill.
In one embodiment, the peptides can be synthesized by the solid phase peptide synthesis procedure using a benzhyderylamine resin (Beckman Bioproducts, 0.59 mmol of NH 2 /g of resin) as the solid support. The COOH terminal amino acid (e.g., t-butylcarbonyl-Phe) is attached to the solid support through a 4-(oxymethyl)phenacetyl group. This is a more stable linkage than the conventional benzyl ester linkage, yet the finished peptide can still be cleaved by hydrogenation. Transfer hydrogenation using formic acid as the hydrogen donor can be used for this purpose.
It is noted that in the chemical synthesis of peptides, particularly peptides comprising D amino acids, the synthesis usually produces a number of truncated peptides in addition to the desired full-length product. Thus, the peptides are typically purified using, e.g., HPLC.
D-amino acids, beta amino acids, non-natural amino acids, and the like can be incorporated at one or more positions in the peptide simply by using the appropriately derivatized amino acid residue in the chemical synthesis. Modified residues for solid phase peptide synthesis are commercially available from a number of suppliers (see, e.g., Advanced Chem Tech, Louisville; Nova Biochem, San Diego; Sigma, St Louis; Bachem Calif. Inc., Torrance, etc.). The D-form and/or otherwise modified amino acids can be completely omitted or incorporated at any position in the peptide as desired. Thus, for example, in certain embodiments, the peptide can comprise a single modified acid, while in other embodiments, the peptide comprises at least two, generally at least three, more generally at least four, most generally at least five, preferably at least six, more preferably at least seven or even all modified amino acids. In certain embodiments, essentially every amino acid is a D-form amino acid.
As indicated above, the peptides and/or fusion proteins of this invention can also be recombinantly expressed. Accordingly, in certain embodiments, the antimicrobial peptides and/or targeting moieties, and/or fusion proteins of this invention are synthesized using recombinant expression systems. Generally this involves creating a DNA sequence that encodes the desired peptide or fusion protein, placing the DNA in an expression cassette under the control of a particular promoter, expressing the peptide or fusion protein in a host, isolating the expressed peptide or fusion protein and, if required, renaturing the peptide or fusion protein.
DNA encoding the peptide(s) or fusion protein(s) described herein can be prepared by any suitable method as described above, including, for example, cloning and restriction of appropriate sequences or direct chemical synthesis.
This nucleic acid can be easily ligated into an appropriate vector containing appropriate expression control sequences (e.g. promoter, enhancer, etc.), and, optionally, containing one or more selectable markers (e.g. antibiotic resistance genes).
The nucleic acid sequences encoding the peptides or fusion proteins described herein can be expressed in a variety of host cells, including, but not limited to, E. coli , other bacterial hosts, yeast, fungus, and various higher eukaryotic cells such as insect cells (e.g. SF3), the COS, CHO and HeLa cells lines and myeloma cell lines. The recombinant protein gene will typically be operably linked to appropriate expression control sequences for each host. For E. coli this can include a promoter such as the T7, trp, or lambda promoters, a ribosome binding site and preferably a transcription termination signal. For eukaryotic cells, the control sequences can include a promoter and often an enhancer (e.g., an enhancer derived from immunoglobulin genes, SV40, cytomegalovirus, etc.), and a polyadenylation sequence, and may include splice donor and acceptor sequences.
The plasmids can be transferred into the chosen host cell by well-known methods such as calcium chloride transformation for E. coli and calcium phosphate treatment or electroporation for mammalian cells. Cells transformed by the plasmids can be selected by resistance to antibiotics conferred by genes contained on the plasmids, such as the amp, gpt, neo and hyg genes.
Once expressed, the recombinant peptide(s) or fusion protein(s) can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, gel electrophoresis and the like (see, generally, R. Scopes, (1982) Protein Purification , Springer-Verlag, N.Y.; Deutscher (1990) Methods in Enzymology Vol. 182 : Guide to Protein Purification ., Academic Press, Inc. N.Y.). Substantially pure compositions of at least about 90 to 95% homogeneity are preferred, and 98 to 99% or more homogeneity are most preferred.
One of skill in the art would recognize that after chemical synthesis, biological expression, or purification, the peptide(s) or fusion protein(s) may possess a conformation substantially different than desired native conformation. In this case, it may be necessary to denature and reduce the peptide or fusion protein and then to cause the molecule to re-fold into the preferred conformation. Methods of reducing and denaturing proteins and inducing re-folding are well known to those of skill in the art (see, e.g., Debinski et al. (1993) J. Biol. Chem., 268: 14065-14070; Kreitman and Pastan (1993) Bioconjug. Chem., 4: 581-585; and Buchner, et al., (1992) Anal. Biochem., 205: 263-270). Debinski et al., for example, describes the denaturation and reduction of inclusion body proteins in guanidine-DTE. The protein is then refolded in a redox buffer containing oxidized glutathione and L-arginine.
One of skill would recognize that modifications can be made to the peptide(s) and/or fusion protein(s) proteins without diminishing their biological activity. Some modifications may be made to facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications are well known to those of skill in the art and include, for example, a methionine added at the amino terminus to provide an initiation site, or additional amino acids (e.g., poly His) placed on either terminus to create conveniently located restriction sites or termination codons or purification sequences.
D) Joining Targeting Moieties to Effectors.
i. Chemical Conjugation.
Chimeric moieties are formed by joining one or more of the targeting moieties described herein to one or more effectors. In certain embodiments the targeting moieties are attached directly to the effector(s) via naturally occurring reactive groups or the targeting moiety and/or the effector(s) can be functionalized to provide such reactive groups.
In various embodiments the targeting moieties are attached to effector(s) via one or more linking agents. Thus, in various embodiments the targeting moieties and the effector(s) can be conjugated via a single linking agent or multiple linking agents. For example, the targeting moiety and the effector can be conjugated via a single multifunctional (e.g., bi-, tri-, or tetra-) linking agent or a pair of complementary linking agents. In another embodiment, the targeting moiety and the effector are conjugated via two, three, or more linking agents. Suitable linking agents include, but are not limited to, e.g., functional groups, affinity agents, stabilizing groups, and combinations thereof
In certain embodiments the linking agent is or comprises a functional group. Functional groups include monofunctional linkers comprising a reactive group as well as multifunctional crosslinkers comprising two or more reactive groups capable of forming a bond with two or more different functional targets (e.g., labels, proteins, macromolecules, semiconductor nanocrystals, or substrate). In some preferred embodiments, the multifunctional crosslinkers are heterobifunctional crosslinkers comprising two or more different reactive groups.
Suitable reactive groups include, but are not limited to thiol (—SH), carboxylate (COOH), carboxyl (—COOH), carbonyl, amine (NH 2 ), hydroxyl (—OH), aldehyde (—CHO), alcohol (ROH), ketone (R 2 CO), active hydrogen, ester, sulfhydryl (SH), phosphate (—PO 3 ), or photoreactive moieties. Amine reactive groups include, but are not limited to e.g., isothiocyanates, isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes and glyoxals, epoxides and oxiranes, carbonates, arylating agents, imidoesters, carbodiimides, and anhydrides. Thiol-reactive groups include, but are not limited to e.g., haloacetyl and alkyl halide derivates, maleimides, aziridines, acryloyl derivatives, arylating agents, and thiol-disulfides exchange reagents. Carboxylate reactive groups include, but are not limited to e.g., diazoalkanes and diazoacetyl compounds, such as carbonyldiimidazoles and carbodiimides. Hydroxyl reactive groups include, but are not limited to e.g., epoxides and oxiranes, carbonyldiimidazole, oxidation with periodate, N,N′-disuccinimidyl carbonate or N-hydroxylsuccimidyl chloroformate, enzymatic oxidation, alkyl halogens, and isocyanates. Aldehyde and ketone reactive groups include, but are not limited to e.g., hydrazine derivatives for schiff base formation or reduction amination. Active hydrogen reactive groups include, but are not limited to e.g., diazonium derivatives for mannich condensation and iodination reactions. Photoreactive groups include, but are not limited to e.g., aryl azides and halogenated aryl azides, benzophenones, diazo compounds, and diazirine derivatives.
Other suitable reactive groups and classes of reactions useful in forming chimeric moieties include those that are well known in the art of bioconjugate chemistry. Currently favored classes of reactions available with reactive chelates are those which proceed under relatively mild conditions. These include, but are not limited to, nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions), and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March (1985) Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York, Hermanson (1996) Bioconjugate Techniques , Academic Press, San Diego; and Feeney et al. (1982) Modification of Proteins; Advances in Chemistry Series , Vol. 198, American Chemical Society, Washington, D.C.
In certain embodiments, the linking agent comprises a chelator. For example, the chelator comprising the molecule, DOTA (DOTA=1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane), can readily be labeled with a radiolabel, such as Gd 3+ and 64 Cu, resulting in Gd 3+ -DOTA and 64 Cu-DOTA respectively, attached to the targeting moiety. Other suitable chelates are known to those of skill in the art, for example, 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA) derivatives being among the most well known (see, e.g., Lee et al. (1997) Nucl Med Biol. 24: 2225-23019).
A “linker” or “linking agent” as used herein, is a molecule that is used to join two or more molecules. In certain embodiments the linker is typically capable of forming covalent bonds to both molecule(s) (e.g., the targeting moiety and the effector). Suitable linkers are well known to those of skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers. In certain embodiments the linkers can be joined to the constituent amino acids through their side groups (e.g., through a disulfide linkage to cysteine). However, in certain embodiments, the linkers will be joined to the alpha carbon amino and carboxyl groups of the terminal amino acids.
A bifunctional linker having one functional group reactive with a group on one molecule (e.g., a targeting peptide), and another group reactive on the other molecule (e.g., an antimicrobial peptide), can be used to form the desired conjugate. Alternatively, derivatization can be performed to provide functional groups. Thus, for example, procedures for the generation of free sulfhydryl groups on peptides are also known (See U.S. Pat. No. 4,659,839).
In certain embodiments the linking agent is a heterobifunctional crosslinker comprising two or more different reactive groups that form a heterocyclic ring that can interact with a peptide. For example, a heterobifunctional crosslinker such as cysteine may comprise an amine reactive group and a thiol-reactive group can interact with an aldehyde on a derivatized peptide. Additional combinations of reactive groups suitable for heterobifunctional crosslinkers include, for example, amine- and sulfhydryl reactive groups; carbonyl and sulfhydryl reactive groups; amine and photoreactive groups; sulfhydryl and photoreactive groups; carbonyl and photoreactive groups; carboxylate and photoreactive groups; and arginine and photoreactive groups. In one embodiment, the heterobifunctional crosslinker is SMCC.
Many procedures and linker molecules for attachment of various molecules to peptides or proteins are known (see, e.g., European Patent Application No. 188,256; U.S. Pat. Nos. 4,671,958, 4,659,839, 4,414,148, 4,699,784; 4,680,338; 4,569,789; and 4,589,071; and Borlinghaus et al. (1987) Cancer Res. 47: 4071-4075). Illustrative linking protocols are provided herein in Examples 2 and 3.
ii. Fusion Proteins.
In certain embodiments where the targeting moiety and effector are both peptides or both comprise peptides, the chimeric moiety can be chemically synthesized or recombinantly expressed as a fusion protein (i.e., a chimeric fusion protein).
In certain embodiments the chimeric fusion proteins are synthesized using recombinant DNA methodology. Generally this involves creating a DNA sequence that encodes the fusion protein, placing the DNA in an expression cassette under the control of a particular promoter, expressing the protein in a host, isolating the expressed protein and, if required, renaturing the protein.
DNA encoding the fusion proteins can be prepared by any suitable method, including, for example, cloning and restriction of appropriate sequences or direct chemical synthesis by methods such as the phosphotriester method of Narang et al. (1979) Meth. Enzymol. 68: 90-99; the phosphodiester method of Brown et al. (1979) Meth. Enzymol. 68: 109-151; the diethylphosphoramidite method of Beaucage et al. (1981) Tetra. Lett., 22: 1859-1862; and the solid support method of U.S. Pat. No. 4,458,066.
Chemical synthesis produces a single stranded oligonucleotide. This can be converted into double stranded DNA by hybridization with a complementary sequence or by polymerization with a DNA polymerase using the single strand as a template. One of skill would recognize that while chemical synthesis of DNA is limited to sequences of about 100 bases, longer sequences can be obtained by the ligation of shorter sequences.
Alternatively, subsequences can be cloned and the appropriate subsequences cleaved using appropriate restriction enzymes. The fragments can then be ligated to produce the desired DNA sequence.
In certain embodiments, DNA encoding fusion proteins of the present invention may be cloned using DNA amplification methods such as polymerase chain reaction (PCR). Thus, for example, the nucleic acid encoding a targeting antibody, a targeting peptide, and the like is PCR amplified, using a sense primer containing the restriction site for NdeI and an antisense primer containing the restriction site for HindIII. This produces a nucleic acid encoding the targeting sequence and having terminal restriction sites. Similarly an effector and/or effector/linker/spacer can be provided having complementary restriction sites. Ligation of sequences and insertion into a vector produces a vector encoding the fusion protein.
While the targeting moieties and effector(s) can be directly joined together, one of skill will appreciate that they can be separated by a peptide spacer/linker consisting of one or more amino acids. Generally the spacer will have no specific biological activity other than to join the proteins or to preserve some minimum distance or other spatial relationship between them. However, the constituent amino acids of the spacer may be selected to influence some property of the molecule such as the folding, net charge, or hydrophobicity.
The nucleic acid sequences encoding the fusion proteins can be expressed in a variety of host cells, including E. coli , other bacterial hosts, yeast, and various higher eukaryotic cells such as the COS, CHO and HeLa cells lines and myeloma cell lines. The recombinant protein gene will be operably linked to appropriate expression control sequences for each host. For E. coli this includes a promoter such as the T7, trp, or lambda promoters, a ribosome binding site and preferably a transcription termination signal. For eukaryotic cells, the control sequences will include a promoter and preferably an enhancer derived from immunoglobulin genes, SV40, cytomegalovirus, etc., and a polyadenylation sequence, and may include splice donor and acceptor sequences.
The plasmids can be transferred into the chosen host cell by well-known methods such as calcium chloride transformation for E. coli and calcium phosphate treatment or electroporation for mammalian cells. Cells transformed by the plasmids can be selected by resistance to antibiotics conferred by genes contained on the plasmids, such as the amp, gpt, neo and hyg genes.
Once expressed, the recombinant fusion proteins can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, gel electrophoresis and the like (see, generally, R. Scopes (1982) Protein Purification , Springer-Verlag, N.Y.; Deutscher (1990) Methods in Enzymology Vol. 182 : Guide to Protein Purification ., Academic Press, Inc. N.Y.). Substantially pure compositions of at least about 90 to 95% homogeneity are preferred, and 98 to 99% or more homogeneity are most preferred for pharmaceutical uses. Once purified, partially or to homogeneity as desired, the polypeptides may then be used therapeutically.
One of skill in the art would recognize that after chemical synthesis, biological expression, or purification, the fusion protein may possess a conformation substantially different than the native conformations of the constituent polypeptides. In this case, it may be necessary to denature and reduce the polypeptide and then to cause the polypeptide to re-fold into the preferred conformation. Methods of reducing and denaturing proteins and inducing re-folding are well known to those of skill in the art (See, Debinski et al. (1993) J. Biol. Chem., 268: 14065-14070; Kreitman and Pastan (1993) Bioconjug. Chem., 4: 581-585; and Buchner, et al. (1992) Anal. Biochem., 205: 263-270).
One of skill would recognize that modifications can be made to the fusion proteins without diminishing their biological activity. Some modifications may be made to facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications are well known to those of skill in the art and include, for example, a methionine added at the amino terminus to provide an initiation site, or additional amino acids placed on either terminus to create conveniently located restriction sites or termination codons.
As indicated above, in various embodiments a peptide linker/spacer is used to join the one or more targeting moieties to one or more effector(s). In various embodiments the peptide linker is relatively short, typically less than about 10 amino acids, preferably less than about 8 amino acids and more preferably about 3 to about 5 amino acids. Suitable illustrative linkers include, but are not limited to PSGSP ((SEQ ID NO:3209), ASASA (SEQ ID NO: 3210), or GGG. In certain embodiments longer linkers such as (GGGGS) 3 (SEQ ID NO:3211) can be used. Illustrative peptide linkers and other linkers are shown in Table 16.





TABLE 16



Illustrative peptide and non-peptide linkers.




Linker
SEQ ID NO:



AAA




GGG




GGGG
3212



SGG




GGSGGS
3213



SAT




PYP




PSPSP
3214



ASA




ASASA
3215



PSPSP
3216



KKKK
3217



RRRR
3218



GGGGS
3219



GGGGS GGGGS
3220



GGGGS GGGGS GGGGS
3221



GGGGS GGGGS GGGGS GGGGS
3222



GGGGS GGGGS GGGGS GGGGS GGGGS
3223



GGGGS GGGGS GGGGS GGGGS GGGGS GGGGS
3224



2-nitrobenzene or O-nitrobenzyl




Nitropyridyl disulfide




Dioleoylphosphatidylethanolamine (DOPE)




S-acetylmercaptosuccinic acid




1, 4, 7, 10-tetraa7acyclododecane-1, 4, 7, 10-tetracetic acid (DOTA)




β-glucuronide and β-glucuronide variants




Poly(alkylacrylic acid)




Benzene-based linkers (for example: 2,5-Bis(hexyloxy)-1,4-bis[2,5-


bis(hexyloxy)-4-formyl-phenylenevinylene]benzene) and like


molecules




Disulfide linkages




Poly(amidoamine) or like dendrimers linking multiple target


and killing peptides in one molecule




Carbon nanotubes




Hydrazone and hydrazone variant linkers




PEG of any chain length




Succinate, formate, acetate butyrate, other like organic acids




Aldols, alcohols, or enols




Peroxides




alkane or alkene groups of any chain length




One or more porphyrin or dye molecules containing free amide and


carboxylic acid groups




One or more DNA or RNA nucleotides, including polyamine and


polycarboxyl-containing variants




Inulin, sucrose, glucose, or other single, di or polysaccharides




Linoleic acid or other polyunsaturated fatty acids




Variants of any of the above linkers containing halogen or thiol


groups



(All amino-acid-based linkers could be L, D, combinations of L and D forms, β-form, and the like)










































































































E) Multiple Targeting Moieties and/or Effectors.
As indicated above, in certain embodiments, the chimeric moieties described herein comprise multiple targeting moieties attached to a single effector or multiple effectors attached to a single targeting moiety, or multiple targeting moieties attached to multiple effectors.
Where the chimeric construct is a fusion protein this is easily accomplished by providing multiple domains that are targeting domains attached to one or more effector domains. FIG. 14 schematically illustrates a few, but not all, configurations. In various embodiments the multiple targeting domains and/or multiple effector domains can be attached to each other directly or can be separated by linkers (e.g., amino acid or peptide linkers as described above).
When the chimeric construct is a chemical conjugate linear or branched configurations (e.g., as illustrated in FIG. 14 ) are readily produced by using branched or multifunctional linkers and/or a plurality of different linkers.
F) Protecting Groups.
While the various peptides (e.g., targeting peptides, antimicrobial peptides, STAMPs) described herein may be shown with no protecting groups, in certain embodiments they can bear one, two, three, four, or more protecting groups. In various embodiments, the protecting groups can be coupled to the C- and/or N-terminus of the peptide(s) and/or to one or more internal residues comprising the peptide(s) (e.g., one or more R-groups on the constituent amino acids can be blocked). Thus, for example, in certain embodiments, any of the peptides described herein can bear, e.g., an acetyl group protecting the amino terminus and/or an amide group protecting the carboxyl terminus. One example of such a protected peptide is the 1845L6-21 STAMP having the amino acid sequence KFINGVLSQFVLERK PYP KLFKFLRKHLL * (SEQ ID NO:3225), where the asterisk indicates an amidated carboxyl terminus. Of course, this protecting group can be can be eliminated and/or substituted with another protecting group as described herein.
Without being bound by a particular theory, it was discovered that addition of a protecting group, particularly to the carboxyl and in certain embodiments the amino terminus can improve the stability and efficacy of the peptide.
A wide number of protecting groups are suitable for this purpose. Such groups include, but are not limited to acetyl, amide, and alkyl groups with acetyl and alkyl groups being particularly preferred for N-terminal protection and amide groups being preferred for carboxyl terminal protection. In certain particularly preferred embodiments, the protecting groups include, but are not limited to alkyl chains as in fatty acids, propionyl, formyl, and others. Particularly preferred carboxyl protecting groups include amides, esters, and ether-forming protecting groups. In one preferred embodiment, an acetyl group is used to protect the amino terminus and an amide group is used to protect the carboxyl terminus. These blocking groups enhance the helix-forming tendencies of the peptides. Certain particularly preferred blocking groups include alkyl groups of various lengths, e.g., groups having the formula: CH 3 —(CH 2 ) n —CO— where n ranges from about 1 to about 20, preferably from about 1 to about 16 or 18, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.
In certain embodiments, the protecting groups include, but are not limited to alkyl chains as in fatty acids, propionyl, formyl, and others. Particularly preferred carboxyl protecting groups include amides, esters, and ether-forming protecting groups. In one embodiment, an acetyl group is used to protect the amino terminus and/or an amino group is used to protect the carboxyl terminus (i.e., amidated carboxyl terminus). In certain embodiments blocking groups include alkyl groups of various lengths, e.g., groups having the formula: CH 3 —(CH 2 ) n —CO— where n ranges from about 3 to about 20, preferably from about 3 to about 16, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.
In certain embodiments, the acid group on the C-terminal can be blocked with an alcohol, aldehyde or ketone group and/or the N-terminal residue can have the natural amide group, or be blocked with an acyl, carboxylic acid, alcohol, aldehyde, or ketone group.
Other protecting groups include, but are not limited to Fmoc, t-butoxycarbonyl (t-BOC), 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, xanthyl (Xan), trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO), benzyl (Bzl), benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl—Z), 2-bromobenzyloxycarbonyl (2-Br—Z), Benzyloxymethyl (Bom), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), Acetyl (Ac), and Trifluoroacetyl (TFA).
Protecting/blocking groups are well known to those of skill as are methods of coupling such groups to the appropriate residue(s) comprising the peptides of this invention (see, e.g., Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. Somerset, N.J.). In illustrative embodiment, for example, acetylation is accomplished during the synthesis when the peptide is on the resin using acetic anhydride. Amide protection can be achieved by the selection of a proper resin for the synthesis. For example, a rink amide resin can be used. After the completion of the synthesis, the semipermanent protecting groups on acidic bifunctional amino acids such as Asp and Glu and basic amino acid Lys, hydroxyl of Tyr are all simultaneously removed. The peptides released from such a resin using acidic treatment comes out with the n-terminal protected as acetyl and the carboxyl protected as NH 2 and with the simultaneous removal of all of the other protecting groups.
Where amino acid sequences are disclosed herein, amino acid sequences comprising, one or more protecting groups, e.g., as described above (or any other commercially available protecting groups for amino acids used, e.g., in boc or fmoc peptide synthesis) are also contemplated.
G) Peptide Circularization.
In certain embodiments the peptides described herein (e.g., AMPs, compound AMPs, STAMPs, etc.) are circularized/cyclized to produce cyclic peptides. Cyclic peptides, as contemplated herein, include head/tail, head/side chain, tail/side chain, and side chain/side chain cyclized peptides. In addition, peptides contemplated herein include homodet, containing only peptide bonds, and heterodet containing in addition disulfide, ester, thioester-bonds, or other bonds.
The cyclic peptides can be prepared using virtually any art-known technique for the preparation of cyclic peptides. For example, the peptides can be prepared in linear or non-cyclized form using conventional solution or solid phase peptide syntheses and cyclized using standard chemistries. Preferably, the chemistry used to cyclize the peptide will be sufficiently mild so as to avoid substantially degrading the peptide. Suitable procedures for synthesizing the peptides described herein as well as suitable chemistries for cyclizing the peptides are well known in the art.
In various embodiments cyclization can be achieved via direct coupling of the N- and C-terminus to form a peptide (or other) bond, but can also occur via the amino acid side chains. Furthermore it can be based on the use of other functional groups, including but not limited to amino, hydroxy, sulfhydryl, halogen, sulfonyl, carboxy, and thiocarboxy. These groups can be located at the amino acid side chains or be attached to their N- or C-terminus.
Accordingly, it is to be understood that the chemical linkage used to covalently cyclize the peptides of the invention need not be an amide linkage. In many instances it may be desirable to modify the N- and C-termini of the linear or non-cyclized peptide so as to provide, for example, reactive groups that may be cyclized under mild reaction conditions. Such linkages include, by way of example and not limitation amide, ester, thioester, CH 2 —NH, etc. Techniques and reagents for synthesizing peptides having modified termini and chemistries suitable for cyclizing such modified peptides are well-known in the art.
Alternatively, in instances where the ends of the peptide are conformationally or otherwise constrained so as to make cyclization difficult, it may be desirable to attach linkers to the N- and/or C-termini to facilitate peptide cyclization. Of course, it will be appreciated that such linkers will bear reactive groups capable of forming covalent bonds with the termini of the peptide. Suitable linkers and chemistries are well-known in the art and include those previously described.
Cyclic peptides and depsipeptides (heterodetic peptides that include ester (depside) bonds as part of their backbone) have been well characterized and show a wide spectrum of biological activity. The reduction in conformational freedom brought about by cyclization often results in higher receptor-binding affinities. Frequently in these cyclic compounds, extra conformational restrictions are also built in, such as the use of D- and N-alkylated-amino acids, α,β-dehydro amino acids or α,α-disubstituted amino acid residues.
Methods of forming disulfide linkages in peptides are well known to those of skill in the art (see, e.g., Eichler and Houghten (1997) Protein Pept. Lett. 4: 157-164). Reference may also be made to Marlowe (1993) Biorg. Med. Chem. Lett. 3: 437-44 who describes peptide cyclization on TFA resin using trimethylsilyl (TMSE) ester as an orthogonal protecting group; Pallin and Tam (1995) J. Chem. Soc. Chem. Comm. 2021-2022) who describe the cyclization of unprotected peptides in aqueous solution by oxime formation; Algin et al. (1994) Tetrahedron Lett. 35: 9633-9636 who disclose solid-phase synthesis of head-to-tail cyclic peptides via lysine side-chain anchoring; Kates et al. (1993) Tetrahedron Lett. 34: 1549-1552 who describe the production of head-to-tail cyclic peptides by three-dimensional solid phase strategy; Tumelty et al. (1994) J. Chem. Soc. Chem. Comm. 1067-1068, who describe the synthesis of cyclic peptides from an immobilized activated intermediate, where activation of the immobilized peptide is carried out with N-protecting group intact and subsequent removal leading to cyclization; McMurray et al. (1994) Peptide Res. 7: 195-206) who disclose head-to-tail cyclization of peptides attached to insoluble supports by means of the side chains of aspartic and glutamic acid; Hruby et al. (1994) Reactive Polymers 22: 231-241) who teach an alternate method for cyclizing peptides via solid supports; and Schmidt and Langer (1997) J. Peptide Res. 49: 67-73, who disclose a method for synthesizing cyclotetrapeptides and cyclopentapeptides.
These methods of peptide cyclization are illustrative and non-limiting. Using the teaching provide herein, other cyclization methods will be available to one of skill in the art.
H) Identification/Verification of Active Peptides
The active AMPs, STAMPs and the like can be identified and/or validated using an in vitro screening assay. Indeed, in many instances the AMPs and/or STAMPS described herein will be used in vitro as preservatives, topical antimicrobial treatments, and the like. Additionally, despite certain apparent limitations of in vitro susceptibility tests, clinical data indicate that a good correlation exists between minimal inhibitory concentration (MIC) test results and in vivo efficacy of antibiotic compounds (see, e.g., Murray et al. (1994) Antimicrobial Susceptibility Testing, Poupard et al., eds., Plenum Press, New York; Knudsen et al. (1995) Antimicrob. Agents Chemother. 39(6): 1253-1258; and the like). Thus, AMPs useful for treating infections and diseases related thereto are also conveniently identified by demonstrated in vitro antimicrobial activity against specified microbial targets, e.g., as illustrated in Table 4).
Typically, the in vitro antimicrobial activity of antimicrobial agents is tested using standard NCCLS bacterial inhibition assays, or MIC tests (see, National Committee on Clinical Laboratory Standards “Performance Standards for Antimicrobial Susceptibility Testing,” NCCLS Document M100-S5 Vol. 14, No. 16, December 1994; “Methods for dilution antimicrobial susceptibility test for bacteria that grow aerobically-Third Edition,” Approved Standard M7-A3, National Committee for Clinical Standards, Villanova, Pa.).
It will be appreciated that other assays as are well known in the art or that will become apparent to those having skill in the art upon review of this disclosure may also be used to identify active AMPs. Such assays include, for example, the assay described in Lehrer et al. (1988) J. Immunol. Meth., 108: 153 and Steinberg and Lehrer, “Designer Assays for Antimicrobial Peptides: Disputing the ‘One Size Fits All’ Theory,” In: Antibacterial Peptide Protocols, Shafer, Ed., Humana Press, N.J. Generally, active peptides of the invention will exhibit MICs (as measured using the assays described in the examples) of less than about 100 preferably less than about 80 or 60 more preferably about 50 μM or less, about 25 μM or less, or about 15 μM or less, or about 10 μM or less.
IV. Administration and Formulations.
A) Pharmaceutical Formulations.
In certain embodiments, the antimicrobial peptides and/or the chimeric constructs (e.g., targeting moieties attached to antimicrobial peptide(s), targeting moieties attached to detectable label(s), etc.) are administered to a mammal in need thereof, to a cell, to a tissue, to a composition (e.g., a food), etc.). In various embodiments the compositions can be administered to detect and/or locate, and/or quantify the presence of particular microorganisms, microorganism populations, biofilms comprising particular microorganisms, and the like. In various embodiments the compositions can be administered to inhibit particular microorganisms, microorganism populations, biofilms comprising particular microorganisms, and the like.
These active agents (antimicrobial peptides and/or chimeric moieties) can be administered in the “native” form or, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method(s). Salts, esters, amides, prodrugs and other derivatives of the active agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. N.Y. Wiley-Interscience.
Methods of formulating such derivatives are known to those of skill in the art. For example, the disulfide salts of a number of delivery agents are described in PCT Publication WO 2000/059863 which is incorporated herein by reference. Similarly, acid salts of therapeutic peptides, peptoids, or other mimetics, and can be prepared from the free base using conventional methodology that typically involves reaction with a suitable acid. Generally, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto. The resulting salt either precipitates or can be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include, but are not limited to both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt can be reconverted to the free base by treatment with a suitable base. Certain particularly preferred acid addition salts of the active agents herein include halide salts, such as may be prepared using hydrochloric or hydrobromic acids. Conversely, preparation of basic salts of the active agents of this invention are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. In certain embodiments basic salts include alkali metal salts, e.g., the sodium salt, and copper salts.
For the preparation of salt forms of basic drugs, the pKa of the counterion is preferably at least about 2 pH lower than the pKa of the drug. Similarly, for the preparation of salt forms of acidic drugs, the pKa of the counterion is preferably at least about 2 pH higher than the pKa of the drug. This permists the counterion to bring the solution's pH to a level lower than the pHmax to reach the salt plateau, at which the solubility of salt prevails over the solubility of free acid or base. The generalized rule of difference in pKa units of the ionizable group in the active pharmaceutical ingredient (API) and in the acid or base is meant to make the proton transfer energetically favorable. When the pKa of the API and counterion are not significantly different, a solid complex may form but may rapidly disproportionate (i.e., break down into the individual entities of drug and counterion) in an aqueous environment.
Preferably, the counterion is a pharmaceutically acceptable counterion. Suitable anionic salt forms include, but are not limited to acetate, benzoate, benzylate, bitartrate, bromide, carbonate, chloride, citrate, edetate, edisylate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), phosphate and diphosphate, salicylate and disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide, valerate, and the like, while suitable cationic salt forms include, but are not limited to aluminum, benzathine, calcium, ethylene diamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, zinc, and the like.
In various embodiments preparation of esters typically involves functionalization of hydroxyl and/or carboxyl groups that are present within the molecular structure of the active agent. In certain embodiments, the esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties that are derived from carboxylic acids of the formula RCOOH where R is alky, and preferably is lower alkyl. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
Amides can also be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
In various embodiments, the active agents identified herein are useful for parenteral, topical, oral, nasal (or otherwise inhaled), rectal, or local administration, such as by aerosol or transdermally, for detection and/or quantification, and or localization, and/or prophylactic and/or therapeutic treatment of infection (e.g., microbial infection). The compositions can be administered in a variety of unit dosage forms depending upon the method of administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, lipid complexes, etc.
The active agents (e.g., antimicrobial peptides and/or chimeric constructs) described herein can also be combined with a pharmaceutically acceptable carrier (excipient) to form a pharmacological composition. In certain embodiments, pharmaceutically acceptable carriers include those approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in/on animals, and more particularly in/on humans. A “carrier” refers to, for example, a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered.
Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s). Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, protection and uptake enhancers such as lipids, compositions that reduce the clearance or hydrolysis of the active agents, or excipients or other stabilizers and/or buffers.
Other physiologically acceptable compounds, particularly of use in the preparation of tablets, capsules, gel caps, and the like include, but are not limited to binders, diluent/fillers, disentegrants, lubricants, suspending agents, and the like.
In certain embodiments, to manufacture an oral dosage form (e.g., a tablet), an excipient (e.g., lactose, sucrose, starch, mannitol, etc.), an optional disintegrator (e.g. calcium carbonate, carboxymethylcellulose calcium, sodium starch glycollate, crospovidone etc.), a binder (e.g. alpha-starch, gum arabic, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, cyclodextrin, etc.), and an optional lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000, etc.), for instance, are added to the active component or components (e.g., active peptide) and the resulting composition is compressed. Where necessary the compressed product is coated, e.g., known methods for masking the taste or for enteric dissolution or sustained release. Suitable coating materials include, but are not limited to ethyl-cellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and Eudragit (Rohm & Haas, Germany; methacrylic-acrylic copolymer).
Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. One skilled in the art would appreciate that the choice of pharmaceutically acceptable carrier(s), including a physiologically acceptable compound depends, for example, on the route of administration of the active agent(s) and on the particular physio-chemical characteristics of the active agent(s).
In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.
In certain therapeutic applications, the compositions of this invention are administered, e.g., topically administered or administered to the oral or nasal cavity, to a patient suffering from infection or at risk for infection or prophylactically to prevent dental caries or other pathologies of the teeth or oral mucosa characterized by microbial infection in an amount sufficient to prevent and/or cure and/or at least partially prevent or arrest the disease and/or its complications. An amount adequate to accomplish this is defined as a “therapeutically effective dose.” Amounts effective for this use will depend upon the severity of the disease and the general state of the patient's health. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient. In any event, the composition should provide a sufficient quantity of the active agents of the formulations of this invention to effectively treat (ameliorate one or more symptoms in) the patient.
The concentration of active agent(s) can vary widely, and will be selected primarily based on activity of the active ingredient(s), body weight and the like in accordance with the particular mode of administration selected and the patient's needs. Concentrations, however, will typically be selected to provide dosages ranging from about 0.1 or 1 mg/kg/day to about 50 mg/kg/day and sometimes higher. Typical dosages range from about 3 mg/kg/day to about 3.5 mg/kg/day, preferably from about 3.5 mg/kg/day to about 7.2 mg/kg/day, more preferably from about 7.2 mg/kg/day to about 11.0 mg/kg/day, and most preferably from about 11.0 mg/kg/day to about 15.0 mg/kg/day. In certain preferred embodiments, dosages range from about 10 mg/kg/day to about 50 mg/kg/day. In certain embodiments, dosages range from about 20 mg to about 50 mg given orally twice daily. It will be appreciated that such dosages may be varied to optimize a therapeutic and/or phophylactic regimen in a particular subject or group of subjects.
In certain embodiments, the active agents of this invention are administered to the oral cavity. This is readily accomplished by the use of lozenges, aersol sprays, mouthwash, coated swabs, and the like.
In certain embodiments, the active agent(s) of this invention are administered topically, e.g., to the skin surface, to a topical lesion or wound, to a surgical site, and the like.
In certain embodiments the active agents of this invention are administered systemically (e.g., orally, or as an injectable) in accordance with standard methods well known to those of skill in the art. In other preferred embodiments, the agents, can also be delivered through the skin using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the active agent(s) are typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer. It will be appreciated that the term “reservoir” in this context refers to a quantity of “active ingredient(s)” that is ultimately available for delivery to the surface of the skin. Thus, for example, the “reservoir” may include the active ingredient(s) in an adhesive on a backing layer of the patch, or in any of a variety of different matrix formulations known to those of skill in the art. The patch may contain a single reservoir, or it may contain multiple reservoirs.
In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. The backing layer in these laminates, which serves as the upper surface of the device, preferably functions as a primary structural element of the “patch” and provides the device with much of its flexibility. The material selected for the backing layer is preferably substantially impermeable to the active agent(s) and any other materials that are present.
Other formulations for topical delivery include, but are not limited to, ointments, gels, sprays, fluids, and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. The specific ointment or cream base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.
As indicated above, various buccal, and sublingual formulations are also contemplated.
In certain embodiments, one or more active agents of the present invention can be provided as a “concentrate”, e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water, alcohol, hydrogen peroxide, or other diluent.
While the invention is described with respect to use in humans, it is also suitable for animal, e.g., veterinary use. Thus certain preferred organisms include, but are not limited to humans, non-human primates, canines, equines, felines, porcines, ungulates, largomorphs, and the like.
B) Nanoemulsion Formulations.
In certain embodiments the targeting peptides, antimicrobial peptides and/or chimeric moieties (e.g., STAMPs) as described herein are formulated in a nanoemulsion. Nanoemulsions include, but are not limited to oil in water (O/W) nanoemulsions, and water in oil (W/O) nanoemulsions. Nanoemulsions can be defined as emulsions with mean droplet diameters ranging from about 20 to about 1000 nm. Usually, the average droplet size is between about 20 nm or 50 nm and about 500 nm. The terms sub-micron emulsion (SME) and mini-emulsion are used as synonyms.
Illustrative oil in water (O/W) nanoemulsions include, but are not limited to:
Surfactant micelles—micelles composed of small molecules surfactants or detergents (e.g., SDS/PBS/2-propanol) which are suitable for predominantly hydrophobic peptides.
Polymer micelles—micelles composed of polymer, copolymer, or block copolymer surfactants (e.g., Pluronic L64/PBS/2-propanol) which are suitable for predominantly hydrophobic peptides;
Blended micelles: micelles in which there is more than one surfactant component or in which one of the liquid phases (generally an alcohol or fatty acid compound) participates in the formation of the micelle (e.g., Octanoic acid/PBS/EtOH) which are suitable for predominantly hydrophobic peptides;
Integral peptide micelles—blended micelles in which the peptide serves as an auxiliary surfactant, forming an integral part of the micelle (e.g., amphipathic peptide/PBS/mineral oil) which are suitable for amphipathic peptides; and
Pickering (solid phase) emulsions—emulsions in which the peptides are associated with the exterior of a solid nanoparticle (e.g., polystyrene nanoparticles/PBS/no oil phase) which are suitable for amphipathic peptides.
Illustrative water in oil (W/O) nanoemulsions include, but are not limited to:
Surfactant micelles—micelles composed of small molecules surfactants or detergents (e.g., dioctyl sulfosuccinate/PBS/2-propanol, Isopropylmyristate/PBS/2-propanol, etc.) which are suitable for predominantly hydrophilic peptides;
Polymer micelles—micelles composed of polymer, copolymer, or block copolymer surfactants (e.g., PLURONIC® L121/PBS/2-propanol), which are suitable for predominantly hydrophilic peptides;
Blended micelles—micelles in which there is more than one surfactant component or in which one of the liquid phases (generally an alcohol or fatty acid compound) participates in the formation of the micelle (e.g., capric/caprylic diglyceride/PBS/EtOH) which are suitable for predominantly hydrophilic peptides;
Integral peptide micelles—blended micelles in which the peptide serves as an auxiliary surfactant, forming an integral part of the micelle (e.g., amphipathic peptide/PBS/polypropylene glycol) which are suitable for amphipathic peptides; and
Pickering (solid phase) emulsions—emulsions in which the peptides are associated with the exterior of a solid nanoparticle (e.g., chitosan nanoparticles/no aqueous phase/mineral oil) which are suitable for amphipathic peptides.
As indicated above, in certain embodiments the nanoemulsions comprise one or more surfactants or detergents. In some embodiments the surfactant is a non-anionic detergent (e.g., a polysorbate surfactant, a polyoxyethylene ether, etc.). Surfactants that find use in the present invention include, but are not limited to surfactants such as the TWEEN®, TRITON®, and TYLOXAPOL® families of compounds.
In certain embodiments the emulsions further comprise one or more cationic halogen containing compounds, including but not limited to, cetylpyridinium chloride. In still further embodiments, the compositions further comprise one or more compounds that increase the interaction (“interaction enhancers”) of the composition with microorganisms (e.g., chelating agents like ethylenediaminetetraacetic acid, or ethylenebis(oxyethylenenitrilo)tetraacetic acid in a buffer).
In some embodiments, the nanoemulsion further comprises an emulsifying agent to aid in the formation of the emulsion. Emulsifying agents include compounds that aggregate at the oil/water interface to form a kind of continuous membrane that prevents direct contact between two adjacent droplets. Certain embodiments of the present invention feature oil-in-water emulsion compositions that may readily be diluted with water to a desired concentration without impairing their anti-pathogenic properties.
In addition to discrete oil droplets dispersed in an aqueous phase, certain oil-in-water emulsions can also contain other lipid structures, such as small lipid vesicles (e.g., lipid spheres that often consist of several substantially concentric lipid bilayers separated from each other by layers of aqueous phase), micelles (e.g., amphiphilic molecules in small clusters of 50-200 molecules arranged so that the polar head groups face outward toward the aqueous phase and the apolar tails are sequestered inward away from the aqueous phase), or lamellar phases (lipid dispersions in which each particle consists of parallel amphiphilic bilayers separated by thin films of water).
These lipid structures are formed as a result of hydrophobic forces that drive apolar residues (e.g., long hydrocarbon chains) away from water. The above lipid preparations can generally be described as surfactant lipid preparations (SLPs). SLPs are minimally toxic to mucous membranes and are believed to be metabolized within the small intestine (see e.g., Hamouda et al., (1998) J. Infect. Disease 180: 1939).
In certain embodiments the emulsion comprises a discontinuous oil phase distributed in an aqueous phase, a first component comprising an alcohol and/or glycerol, and a second component comprising a surfactant or a halogen-containing compound. The aqueous phase can comprise any type of aqueous phase including, but not limited to, water (e.g., dionized water, distilled water, tap water) and solutions (e.g., phosphate buffered saline solution, or other buffer systems). The oil phase can comprise any type of oil including, but not limited to, plant oils (e.g., soybean oil, avocado oil, flaxseed oil, coconut oil, cottonseed oil, squalene oil, olive oil, canola oil, corn oil, rapeseed oil, safflower oil, and sunflower oil), animal oils (e.g., fish oil), flavor oil, water insoluble vitamins, mineral oil, and motor oil. In certain embodiments, the oil phase comprises 30-90 vol % of the oil-in-water emulsion (i.e., constitutes 30-90% of the total volume of the final emulsion), more preferably 50-80%.
In certain embodiments the alcohol, when present, is ethanol.
While the present invention is not limited by the nature of the surfactant, in some preferred embodiments, the surfactant is a polysorbate surfactant (e.g., TWEEN 20®, TWEEN 40®, TWEEN 60®, and TWEEN 80®)), a pheoxypolyethoxyethanol (e.g., TRITON® X-100, X-301, X-165, X-102, and X-200, and TYLOXAPOL®), or sodium dodecyl sulfate, and the like.
In certain embodiments a halogen-containing component is present. the nature of the halogen-containing compound, in some preferred embodiments the halogen-containing compound comprises a chloride salt (e.g., NaCl, KCl, etc.), a cetylpyridinium halide, a cetyltrimethylammonium halide, a cetyldimethylethylammonium halide, a cetyldimethylbenzylammonium halide, a cetyltributylphosphonium halide, dodecyltrimethylammonium halides, tetradecyltrimethylammonium halides, cetylpyridinium chloride, cetyltrimethylammonium chloride, cetylbenzyldimethylammonium chloride, cetylpyridinium bromide, cetyltrimethylammonium bromide, cetyldimethylethylammonium bromide, cetyltributylphosphonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, and the like
In certain embodiments the emulsion comprises a quaternary ammonium compound. Quaternary ammonium compounds include, but are not limited to, N-alkyldimethyl benzyl ammonium saccharinate, 1,3,5-Triazine-1,3,5(2H,4H,6H)-triethanol; 1-Decanaminium, N-decyl-N,N-dimethyl-, chloride (or) Didecyl dimethyl ammonium chloride; 2-(2-(p-(Diisobuyl)cresosxy)ethoxy)ethyl dimethyl benzyl ammonium chloride; 2-(2-(p-(Diisobutyl)phenoxy)ethoxy)ethyl dimethyl benzyl ammonium chloride; alkyl 1 or 3 benzyl-1-(2-hydroxethyl)-2-imidazolinium chloride; alkyl bis(2-hydroxyethyl)benzyl ammonium chloride; alkyl demethyl benzyl ammonium chloride; alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride (100% C12); alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride (50% C14, 40% C12, 10% C16); alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride (55% C14, 23% C12, 20% C16); alkyl dimethyl benzyl ammonium chloride; alkyl dimethyl benzyl ammonium chloride (100% C14); alkyl dimethyl benzyl ammonium chloride (100% C16); alkyl dimethyl benzyl ammonium chloride (41% C14, 28% C12); alkyl dimethyl benzyl ammonium chloride (47% C12, 18% C14); alkyl dimethyl benzyl ammonium chloride (55% C16, 20% C14); alkyl dimethyl benzyl ammonium chloride (58% C14, 28% C16); alkyl dimethyl benzyl ammonium chloride (60% C14, 25% C12); alkyl dimethyl benzyl ammonium chloride (61% C11, 23% C14); alkyl dimethyl benzyl ammonium chloride (61% C12, 23% C14); alkyl dimethyl benzyl ammonium chloride (65% C12, 25% C14); alkyl dimethyl benzyl ammonium chloride (67% C12, 24% C14); alkyl dimethyl benzyl ammonium chloride (67% C12, 25% C14); alkyl dimethyl benzyl ammonium chloride (90% C14, 5% C12); alkyl dimethyl benzyl ammonium chloride (93% C14, 4% C12); alkyl dimethyl benzyl ammonium chloride (95% C16, 5% C18); alkyl dimethyl benzyl ammonium chloride (and) didecyl dimethyl ammonium chloride; alkyl dimethyl benzyl ammonium chloride (as in fatty acids); alkyl dimethyl benzyl ammonium chloride (C12-C16); alkyl dimethyl benzyl ammonium chloride (C12-C18); alkyl dimethyl benzyl and dialkyl dimethyl ammonium chloride; alkyl dimethyl dimethybenzyl ammonium chloride; alkyl dimethyl ethyl ammonium bromide (90% C14, 5% C16, 5% C12); alkyl dimethyl ethyl ammonium bromide (mixed alkyl and alkenyl groups as in the fatty acids of soybean oil); alkyl dimethyl ethylbenzyl ammonium chloride; alkyl dimethyl ethylbenzyl ammonium chloride (60% C14); alkyl dimethyl isoproylbenzyl ammonium chloride (50% C12, 30% C14, 17% C16, 3% C18); alkyl trimethyl ammonium chloride (58% C18, 40% C16, 1% C14, 1% C12); alkyl trimethyl ammonium chloride (90% C18, 10% C16); alkyldimethyl(ethylbenzyl) ammonium chloride (C12-18); Di-(C8-10)-alkyl dimethyl ammonium chlorides; dialkyl dimethyl ammonium chloride; dialkyl dimethyl ammonium chloride; dialkyl dimethyl ammonium chloride; dialkyl methyl benzyl ammonium chloride; didecyl dimethyl ammonium chloride; diisodecyl dimethyl ammonium chloride; dioctyl dimethyl ammonium chloride; dodecyl bis(2-hydroxyethyl) octyl hydrogen ammonium chloride; dodecyl dimethyl benzyl ammonium chloride; dodecylcarbamoyl methyl dimethyl benzyl ammonium chloride; heptadecyl hydroxyethylimidazolinium chloride; hexahydro-1,3,5-thris(2-hydroxyethyl)-s-triazine; myristalkonium chloride (and) Quat RNIUM 14; N,N-Dimethyl-2-hydroxypropylammonium chloride polymer; n-alkyl dimethyl benzyl ammonium chloride; n-alkyl dimethyl ethylbenzyl ammonium chloride; n-tetradecyl dimethyl benzyl ammonium chloride monohydrate; octyl decyl dimethyl ammonium chloride; octyl dodecyl dimethyl ammonium chloride; octyphenoxyethoxyethyl dimethyl benzyl ammonium chloride; oxydiethylenebis (alkyl dimethyl ammonium chloride); quaternary ammonium compounds, dicoco alkyldimethyl, chloride; trimethoxysily propyl dimethyl octadecyl ammonium chloride; trimethoxysilyl quats, trimethyl dodecylbenzyl ammonium chloride; n-dodecyl dimethyl ethylbenzyl ammonium chloride; n-hexadecyl dimethyl benzyl ammonium chloride; n-tetradecyl dimethyl benzyl ammonium chloride; n-tetradecyl dimethyl ethylbenzyl ammonium chloride; and n-octadecyl dimethyl benzyl ammonium chloride.
Nanoemulsion formulations and methods of making such are well known to those of skill in the art and described for example in U.S. Pat. Nos. 7,476,393, 7,468,402, 7,314,624, 6,998,426, 6,902,737, 6,689,371, 6,541,018, 6,464,990, 6,461,625, 6,419,946, 6,413,527, 6,375,960, 6,335,022, 6,274,150, 6,120,778, 6,039,936, 5,925,341, 5,753,241, 5,698,219, an d5,152,923 and in Fanun et al. (2009) Microemulsions: Properties and Applications (Surfactant Science), CRC Press, Boca Ratan Fl.
C) Formulations Optimizing Activity.
In certain embodiments, formulations are selected to optimize binding specificity, and/or binding avidity, and/or antimicrobial activity, and/or stability/conformation of the targeting peptide, antimicrobial peptide, chimeric moiety, and/or STAMP. In this regard, it was a surprising discovery that the activity of certain STAMPs, and presumably the constituent targeting peptides and/or antimicrobial peptides was optimized in the presence of a salt. Accordingly, certain embodiments are contemplated where the targeting peptide and/or antimicrobial peptide, and/or STAMP is formulated in combination with one or more salts. The formulations disclosed herein, however, are not limited to those containing salt(s). Embodiments, are also contemplated where the targeting peptide and/or antimicrobial peptide, and/or STAMP is formulated without the presence of a salt.
In certain embodiments, sodium chloride plus a little potassium chloride resulted in the best activity of the salts tested. However, other salts, e.g., CaCl 2 , MgCl 2 , MnCl 2 also enhanced activity. Accordingly, in certain embodiments, it is contemplated that the targeting peptide(s), and/or antimicrobial peptide(s), and/or chimeric moieties, and/or STAMPs are formulated with one or more salts.
In certain embodiments suitable salts include any of a number of pharmaceutically acceptable salts. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, besylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like (see, e.g., Berge et al. (1977) J. Pharm. Sci. 66: 1-19), although it is noted that citrate salts appear to inhibit the activity of certain STAMPs.
In certain embodiments pharmaceutically acceptable salts of the present invention include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately treating the compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra; and Stahl and Wermuth (2002) Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Zurich, Switzerland).
In various embodiments, the salt is simply a sodium chloride and/or a potassium chloride and can readily be prepared, for example, as a phosphate buffered saline (PBS) solution. In certain embodiments, the salt concentration is comparable to that found in 0.5×PBS to about 2.5×PBS, more preferably from about 0.5×PBS to about 1.5×PBS. In certain embodiments optimum activity has been observed in 1×PBS.
In various embodiments, the pH of the formulation ranges from about pH 5.0 to about pH 8.5, preferably from about pH 6.0 to about pH 8.0, more preferably from about pH 7.0 to about pH 8.0. In certain embodiments the pH is about pH 7.4.
While optimum results have been observed for certain STAMPS using a PBS buffer system, other buffer systems are also acceptable. Such buffers include, but are not limited to sulfate buffers, carbonate buffers, Tris buffers, CHAPS buffers, PIPES buffers, and the like, as long as the salt is included.
In various embodiments, the targeting peptide, and/or antimicrobial peptide, and/or chimeric moiety, and/or STAMP is present in the formulation at a concentration ranging from about 1 nM, to about 1, 10, or 100 mM, more preferably from about 1 nM, about 10 nM, about 100 nM, about 1 or about 10 μM to about 50 about 100 about 200 μm, about 300 about 400 or about 500 preferably from about 1 about 10 about 25 or about 50 μM to about 1 mM, about 10 mM, about 20 mM, or about 5 mM, most preferably from about 10 about 20 or about 50 μM to about 100 μM, about 150 μM, or about 200 μM.
D) Home Health Care/Hygiene Product Formulations.
In certain embodiments, one or more of the targeting peptide(s), and/or antimicrobial peptides (AMPs) and/or chimeric moieties, and/or STAMPS described herein are incorporated into healthcare formulations, e.g., for home use. Such formulations include, but are not limited to toothpaste, mouthwash, tooth whitening strips or solutions, contact lens storage, wetting, or cleaning solutions, dental floss, toothpicks, toothbrush bristles, oral sprays, oral lozenges, nasal sprays, aerosolizers for oral and/or nasal application, wound dressings (e.g., bandages), and the like.
For example, chimeric moieties and/or STAMPs, and/or AMPs directed against S. mutans are well suited for inhibiting frequency or severity of dental caries formation, plaque formation, periodontal disease, and/or halitosis.
Chimeric moieties and/or STAMPs, and/or AMPs directed against Corynebacterium spp, when applied to a skin surface can reduce/eliminate Corynebacterium resulting in a reduction of odors. Such moieties are readily incorporated in soaps, antibiotics, antiseptics, disinfectants, and the like.
The formulation of such health products is well known to those of skill, and the antimicrobial peptides and/or chimeric constructs are simply added to such formulations in an effective dose (e.g., a prophylactic dose to inhibit dental carie formation, etc.).
For example, toothpaste formulations are well known to those of skill in the art. Typically such formulations are mixtures of abrasives and surfactants; anticaries agents, such as fluoride; tartar control ingredients, such as tetrasodium pyrophosphate and methyl vinyl ether/maleic anhydride copolymer; pH buffers; humectants, to prevent dry-out and increase the pleasant mouth feel; and binders, to provide consistency and shape (see, e.g., Table 17). Binders keep the solid phase properly suspended in the liquid phase to prevent separation of the liquid phase out of the toothpaste. They also provide body to the dentifrice, especially after extrusion from the tube onto the toothbrush.
TABLE 17 Typical components of toothpaste. Ingredients Wt % Humectants 40-70 Water 0-50 Buffers/salts/tartar 0.5-10 control Organic thickeners 0.4-2 (gums) Inorganic thickeners 0-12 Abrasives 10-50 Actives (e.g., triclosan) 0.2-1.5 Surfactants 0.5-2 Flavor and sweetener 0.8-1.5
Fluoride sources provide 1000-15000 ppm fluorine.

Table 18 lists typical ingredients used in formulations; the final combination will depend on factors such as ingredient compatibility and cost, local customs, and desired benefits and quality to be delivered in the product. It will be recognized that one or more antimicrobial peptides and/or chimeric constructs described herein can simply be added to such formulations or used in place of one or more of the other ingredients.





TABLE 18



List of typical ingredients.













Tartar


Inorganic



Control

Gums
Thickeners
Abrasives
Surfactants
Humectants
Ingredient



Sodium
Silica
Hydrated
Sodium
Glycerine
Tetrasodium

carboxymethyl
thickeners
silica
lauryl sulfate

pyrophosphate

cellulose

Cellulose ethers
Sodium
Dicalcium
Sodium N-
Sorbitol
Gantrez S-70


aluminum
phosphate
lauryl


silicates
digydrate
sarcosinate

Xanthan Gum
Clays
Calcium
Pluronics
Propylene
Sodium tri-



carbonate

glycol
polyphosphate

Carrageenans

Sodium

Xylitol



bicarbonate

Sodium alginate

Calcium
Sodium
Polyethylene



pyrophosphate
lauryl
glycol




sulfoacetate

Carbopols

Alumina




































One illustrative formulation described in U.S. Pat. No. 6,113,887 comprises (1) a water-soluble bactericide selected from the group consisting of pyridinium compounds, quaternary ammonium compounds and biguanide compounds in an amount of 0.001% to 5.0% by weight, based on the total weight of the composition; (2) a cationically-modified hydroxyethylcellulose having an average molecular weight of 1,000,000 or higher in the hydroxyethylcellulose portion thereof and having a cationization degree of 0.05 to 0.5 mol/glucose in an amount of 0.5% to 5.0% by weight, based on the total weight of the composition; (3) a surfactant selected from the group consisting of polyoxyethylene polyoxypropylene block copolymers and alkylolamide compounds in an amount of 0.5% to 13% by weight, based on the total weight of the composition; and (4) a polishing agent of the non-silica type in an amount of 5% to 50% by weight, based on the total weight of the composition. In certain embodiments, the antimicrobial peptide(s) and/or chimeric construct(s) described herein can be used in place of the bactericide or in combination with the bactericide.
Similarly, mouthwash formulations are also well known to those of skill in the art. Thus, for example, mouthwashes containing sodium fluoride are disclosed in U.S. Pat. Nos. 2,913,373, 3,975,514, and 4,548,809, and in US Patent Publications US 2003/0124068 A1, US 2007/0154410 A1, and the like. Mouthwashes containing various alkali metal compounds are also known: sodium benzoate (WO 9409752); alkali metal hypohalite (US 20020114851A1); chlorine dioxide (CN 1222345); alkali metal phosphate (US 2001/0002252 A1, US 2003/0007937 A1); hydrogen sulfate/carbonate (JP 8113519); cetylpyridium chloride (CPC) (see, e.g., U.S. Pat. No. 6,117,417, U.S. Pat. No. 5,948,390, and JP 2004051511). Mouthwashes containing higher alcohol (see, e.g., US 2002/0064505 A1, US 2003/0175216 A1); hydrogen peroxide (see, e.g., CN 1385145); CO 2 gas bubbles (see, e.g., JP 1275521 and JP 2157215) are also known. In certain embodiments, these and other mouthwash formulations can further comprise one or more of the AMPs or compound AMPs of this invention.
Contact lens storage, wetting, or cleaning solutions, dental floss, toothpicks, toothbrush bristles, oral sprays, oral lozenges, nasal sprays, and aerosolizers for oral and/or nasal application, and the like are also well known to those of skill in the art and can readily be adapted to incorporate one or more antimicrobial peptide(s) and/or chimeric construct(s) described herein.
The foregoing pharmaceutical and/or home healthcare formulations and/or devices are meant to be illustrative and not limiting. Using teaching provided herein, the antimicrobial peptide(s) and/or chimeric construct(s) described herein can readily be incorporated into other products.
E) Illustrative Oral Care Formulations.
The targeting peptide(s), and/or antimicrobial peptide(s), and/or chimeric moieties, and/or STAMPs described herein can be used for a number of applications, e.g., as described above. In certain embodiments anti- S. mutans STAMPs, AMPs, and/or other chimeric moieties can be used to reduce the incidence or severity of dental caries, inhibit plaque formation, reduce halitosis, and the like. Accordingly, in certain embodiments, such moieties are included in devices and formulations for dental applications e.g., tea or other drinks, toothpick coatings, dental floss coatings, toothpaste, gel, mouthwash, varnish, even professional dental products.
In certain embodiments, methods of treating or reducing the incidence, duration, or severity of periodontal disease are provided. The methods can include applying to the gingival crevice or periodontal pocket a composition comprising a targeting peptide, and/or antimicrobial peptide, and/or STAMP, and/or other chimeric moiety as described herein with a carrier/stabilizing agent. In the composition applied, the carrier/stabilizing agent can provide retention, tissue penetration, deposition and sustained release of the active agent (e.g., STAMP) for reducing the population of specific bacterial species within a periodontal biofilm and associated tissues. In certain embodiments, the carrier agent provides penetration and retention into the gingival crevice or periodontal pocket and associated tissues with sustained release of the active agent to enhance the reduction in population of select bacteria within the gingival tissue and dentinal tubule tissue.
In various embodiments, carrier agents can include, but are not limited to polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone, cellulosic-based polymers, ethylene glycol polymers and its copolymers, oxyethylene polymers, polyvinyl alcohol, chitosan and hyaluronan and its copolymers. In an aspect, the carrier agents include hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide co-polymers, chitosan, hyaluronan and its copolymers, or combinations thereof. In another aspect, the carrier agents include hyaluronan or hyaluronic acid and copolymers including salts of hyaluronic acid, esters of hyaluronic acid, cross-linked gels of hyaluronic acid, enzymatic derivatives of hyaluronic acid, chemically modified derivatives of hyaluronic acid or combinations thereof. As used herein, hyaluronic acid broadly refers to naturally occurring, microbial and synthetic derivatives of acidic polysaccharides of various molecular weights constituted by residues of D-glucuronic acid polysaccharides and N-acetyl-D-glucosamine.
In certain embodiments, the active agent (e.g., STAMP, AMP, etc.) and the carrier agent are in the form of an admixture, in the form of a complex, covalently coupled, or a combination thereof. In certain embodiments, the carrier agent comprises a bioadhesive. Suitable bioadhesive carrier agents include, but are not limited to a cellulose based polymer and/or a dextrin. Suitable cellulose based polymers include, but are not limited to hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, or a mixture thereof. In one illustrative embodiment, the bioadhesive carrier agent includes polylactide, polyglycolide, polylactide-co-glycolide, polyethylene glycol, hyaluronan, hyaluronic acid, chitosan, or a mixture thereof. In certain embodiments the bioadhesive carrier agent can include a copolymer comprising polyethylene glycol, hyaluronan, hyaluronic acid, chitosan, or a mixture thereof.
In certain embodiments, the carrier agent penetrates periodontal tissues. Suitable penetrating carrier agents include, but are not limited to hyaluronic acid, a hyaluronic acid derivative, chitosan, a chitosan derivative, or a mixture thereof. In an embodiment, the penetrating carrier agent includes a salt of hyaluronic acid, an ester of hyaluronic acid, an enzymatic derivative of hyaluronic acid, a cross-linked gel of hyaluronic acid, a chemically modified derivative of hyaluronic acid, or a mixture thereof.
V. Microorganism Detection.
As indicated above, the targeting moieties and/or STAMPs are useful in diagnostic compositions and methods to determine the presence or absence and/or to quantify the amount of one or microorganisms present in the environment, in a food stuff, in a biological sample, and the like.
For example, targeting peptide-antimicrobial peptide conjugates (e.g. Specifically targeted antimicrobial peptides (STAMPs)) can be used as diagnostic reagents. STAMPs (and other targeted antimicrobial constructs described herein) have the ability to specifically bind to microorganisms, for example, S. mutans , and permeabilize or disrupt their membrane such that cell impermeable dyes or other reagent (propidium iodide, etc.) may enter the microorganism or intracellular molecules or contents (ATP, DNA, Calcium, etc.) of the targeted microorganism are caused to be released into the environment for analysis. In one method a STAMP, for example, C16G2, can permeabilize or disrupt the membrane of target microorganisms, for example, S. mutans , in a prepared culture or clinical sample by itself, in a biofilm in vitro or in vivo. To the sample a cell impermeable dye (e.g. propidium iodide, etc.) is added to label and allow for detection of those microorganisms targeted by the STAMP. Cell permeable dyes (e.g. SYTO9) can also be added to label and detect the entire population of microorganisms in the sample. Labeled cells can then be quantified by fluorescence microscopy, fluorometry, flow cytometry or other method.
In another example, a STAMP treated sample is mixed with luciferase and luciferin which reacts with the ATP released from the STAMP treated cells and the resulting luminescence is used to detected and quantify targeted cells.
VI. Kits.
In another embodiment this invention provides kits for the inhibition of an infection and/or for the treatment and/or prevention of dental caries in a mammal. The kits typically comprise a container containing one or more of the active agents (i.e., the antimicrobial peptide(s) and/or chimeric construct(s)) described herein. In certain embodiments the active agent(s) can be provided in a unit dosage formulation (e.g., suppository, tablet, caplet, patch, etc.) and/or may be optionally combined with one or more pharmaceutically acceptable excipients.
In certain embodiments the kits comprise one or more of the home healthcare product formulations described herein (e.g., toothpaste, mouthwash, tooth whitening strips or solutions, contact lens storage, wetting, or cleaning solutions, dental floss, toothpicks, toothbrush bristles, oral sprays, oral lozenges, nasal sprays, aerosolizers for oral and/or nasal application, and the like).
In certain embodiments kits are provided for detecting and/or locating and/or quantifying certain target microorganisms and/or cells or tissues comprising certain target microorganisms, and/or prosthesis bearing certain target microorganisms, and/or biofilms comprising certain target microorganisms. In various embodiments these kits typically comprise a chimeric moiety comprising a targeting moiety and a detectable label as described herein and/or a targeting moiety attached to an affinity tag for use in a pretargeting strategy as described herein.
In addition, the kits optionally include labeling and/or instructional materials providing directions (i.e., protocols) for the practice of the methods or use of the “therapeutics” or “prophylactics” or detection reagents of this invention. Certain instructional materials describe the use of one or more active agent(s) of this invention to therapeutically or prophylactically to inhibit or prevent infection and/or to inhibit the formation of dental caries. The instructional materials may also, optionally, teach preferred dosages/therapeutic regiment, counter indications and the like.
While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.
EXAMPLES
The following examples are offered to illustrate, but not to limit the claimed invention.
Example 1
Design and Activity of a “Dual-Targeted” Antimicrobial Peptide
Numerous reports have indicated the important role of human normal flora in the prevention of microbial pathogenesis and disease. Evidence suggests that infections at mucosal surfaces result from the outgrowth of subpopulations or clusters within a microbial community, and are not linked to one pathogenic organism alone. In order to preserve the protective normal flora while treating the majority of infective bacteria in the community, a tunable therapeutic is necessary that can discriminate between benign bystanders and multiple pathogenic organisms. Here we describe the proof-of-principle for such a multi-targeted antimicrobial: a multiple-headed specifically-targeted antimicrobial peptide (MH-STAMP). The completed MH-STAMP, M8(KH)-20, displays specific activity against targeted organisms in vitro ( Pseudomonas aeruginosa and Streptococcus mutans ) and can remove both species from a mixed planktonic culture with little impact against untargeted bacteria. These results demonstrate that a functional, dual-targeted molecule can be constructed from wide-spectrum antimicrobial peptide precursor.
Introduction
For nearly 30 years antimicrobial peptides (AMPs) have been rigorously investigated as alternatives to small molecule antibiotics and potential solutions to the growing crisis of antibiotic resistant bacterial infections (Ganz (2003) Nat Rev Immunol., 3: 710-720; Hancock and Lehrer (1998)., 16: 82-88). Numerous reports have characterized potential AMPs from natural sources, and a great body of work has been carried out designing “tailor-made” AMPs due to the approachable nature of solid-phase peptide synthesis (SPPS) (Genco et al. (2003) Int J Antimicrob Agents, 21: 75-78; He and Eckert (2007) Antimicrob Agents Chemother., 51: 1351-1358). Several examples of the latter have shown remarkable activities in vitro against fungi, Gram-positive and Gram-negative bacteria, as well as some enveloped viruses (Brogden (2005) Nat Rev Microbiol. 3: 238-250).
Unlike small molecule antibiotics that may lose activity when their basic structures are modified even incrementally, peptides are a convenient canvas for molecular alteration. AMPs can be optimized through the incorporation of more or less hydrophobic or charged amino acids, which has been shown to affect selectivity for Gram-positive, Gram-negative or fungal membranes (Muhle and Tam J P (2001) Biochemistry, 40: 5777-5785; Tossi et al. (2000) Biopolymers 55: 4-30). Additionally, lysine residues can be utilized to improve AMP activity per μM. In this approach, multiple AMP chains can be attached to a single peptide scaffold through branching from lysine epsilon-amines (Tam et al. (2992) Eur. J. Biochem., 269: 923-932; Pini et al. (2005) Antimicrob Agents Chemother., 2005; 49: 2665-2672). AMP activity can be specifically tuned through the attachment of a targeting peptide region, as described for a novel class of molecules, the specifically-targeted antimicrobial peptides, or STAMPs (Eckert et al. (2006) Antimicrob Agents Chemother., 50: 3651-3657; Eckert et al. (2006) Antimicrob Agents Chemother., 50: 1480-1488). These chimeric molecules can consist of functionally independent targeting and killing moieties within a linear peptide sequence. A pathogenic bacterium recognized (i.e. bound) by the targeting peptide can be eliminated from a multi-species community with little impact to bystander normal flora. As an extension of this concept, we hypothesized that a STAMP could be constructed with multiple targeting peptide “heads” attached to a single AMP by utilizing a central lysine residue branch point. Potentially, targeting “heads” could be specific for the same pathogen, or have different binding profiles. Utilizing the former approach, microbial resistance evolution linked to a targeting peptide could be inhibited or reduced, as no single microbial population would have the genetic diversity necessary to mutate multiple discrete targeting peptide receptors in one cell (Drake et al. (1998) Genetics 148: 1667-1686).
Multi-headed STAMP (MH-STAMP) molecules with differing bacterial targets may have appeal in treating poly-microbial infections, or where it may be advantageous to remove a cluster of biofilm constituents without utilizing several distinct molecules; for example in the simultaneously treatment of dental caries and periodontitis, or in the eradication of the Propionibacteria spp. and Staphylococcus spp. involved in acne and skin infections, respectively.
In this example, we present the proof-of-principle design, synthesis and in vitro activity of such a MH-STAMP, M8(KH)-20. Previously, we identified two functional STAMP targeting domains, one with specific recognition of the cariogenic pathogen S. mutans (Eckert et al. (2006) Antimicrob Agents Chemother., 50: 3651-3657), and the other with Pseudomonas spp.-level selectivity (Eckert et al. (2006) Antimicrob Agents Chemother., 50: 3833-3838). Conjoined to a normally wide-spectrum linear AMP, we observed antimicrobial effects directed specifically to P. aeruginosa and S. mutans in vitro. Additionally, treatment of mixed bacterial communities with the multi-headed MH-STAMP resulted in the specific eradication of the target organisms with little impact on bystander population levels.
Materials and Methods
Bacterial Strains and Growth Conditions
P. aeruginosa ATCC 15692, Klebsiella pneumoniae KAY 2026 (Sprenger and Lengeler (1984) J Bacteriol., 157: 39-45), Escherichia coli DH5α (pFW5, spectinomycin resistance) (Podbielski et al. (1996) Gene, 177: 137-147), Staphylococcus aureus Newmann (Duthie and Lorenz (1952) J Gen Microbiol., 6: 95-107), and Staphylococcus epidermidis ATCC 35984 were cultivated under aerobic conditions at 37° C. with vigorous shaking. Aerobic Gram-negative organisms were grown in Lauri-Bertaini (LB) broth and Gram-positive bacteria in Brain-heart infusion (BHI) broth. Streptococcus mutans JM11 (spectinomycin resistant, UA140 background) was grown in Todd-Hewitt (TH) broth under anaerobic conditions (80% N2, 15% CO 2 , 5% H2) at 37° C. Merritt et al. (2005) J Microbiol Meth., 61: 161-170. All bacteria were grown overnight to an OD600 of 0.8-1.0 prior to appropriate dilution and antimicrobial testing.
Synthesis of Multi-Head STAMP Peptides
Conventional solid-phase peptide synthesis (SPPS) methodologies were utilized for the construction of all peptides shown in FIG. 15 (Symphony Synthesizer, PTI, Tucson, Ariz.). Chemicals, amino acids, and synthesis resins were purchased from Anaspec (San Jose, Calif.). BD2.20 (FIRKFLKKWLL (SEQ ID NO:3226), amidated c-terminus, mw 1491.92), an antimicrobial peptide developed in our laboratory with robust antimicrobial activity against a number of bacterial species (Table 19), served as the root sequence to which differing targeting peptides were attached: Firstly, BD2.20 was synthesized by SPPS (Rink-Amide-MBHA resin, 0.015 mmol), followed by the stepwise coupling of a functionalized alkane (NH 2 (CH 2 ) 7 COOH), and an Fmoc-protected Lys (side-chain protected with 4-methyltrityl (Mtt)) to the N-terminus. Standard SPPS methods were then employed for the step-wise addition of the S. mutans targeting peptide M8 plus a tri-Gly linker region (TFFRFLNR-GGG (SEQ ID NO:3227)) to the N-terminal of the central Lys. After assembly of Fmoc-M8-GGG-K(Mtt)-(CH 2 ) 7 CO-BD2.20 (SEQ ID NO:3228), the Fmoc group was removed with 25% piperidine in DMF and the N-terminal was re-protected with an acetyl group with Ac 2 O/DIEA (1:1, 20 molar excess) for 2 hours. The Mtt-protected amino group of the central Lys was then selectively exposed with 2% TFA in DCM (1.5 mL) for 15 minutes (three cycles of 5 min). The resulting product was reloaded into the synthesizer and the peptide sequence built from the Lys side-chain was completed with standard Fmoc SPPS methods. As shown in FIG. 15 , the completed MH-STAMP M8(KH)-20 contained the side-chain peptide KH ( Pseudomonas spp.-targeting, KKHRKHRKHRKH-GGG (SEQ ID NO:3229)), while in MH-STAMP M8(BL)-20 a peptide with no bacterial binding (data not shown), BL-1 (DAANEA-GGG), was utilized. BL(KH)-20 was constructed identically to M8(KH)-20, utilizing BL-1 in place of M8 ( FIG. 15 ).





TABLE 19



MICs of MH-STAMPs and component peptides.





MIC (μM)











P. aeruginosa


E. coli


K. pneumoniae


S. mutans


S. epidermidis


S. aureus













BD2.20
14.4 ± 4.40
5.47 ± 1.41
2.98 ± 0.47
2.86 ± 0.60
5.11 ± 1.58
5.625 ± 1.29

M8(KH)-20
11.95 ± 3.32
2.72 ± 0.59
3.13
6.25
3.13
5.64 ± 1.07

M8(BL)-20
50
5.97 ± 0.94
6.88 ± 1.98
6.25
6.25
18.05 ± 6.58

BL(KH)-20
27.5 ± 7.90
6.25
6.25
6.25
6.25
6.25



Average MIC with standard deviation, n = 10 assays.






























Synthesis progression was monitored by the ninhydrin test, and completed peptides cleaved from the resin with 95% TFA utilizing appropriate scavengers, and precipitated in methyl tert-butyl ether. Purification and MH-STAMP quality was confirmed by HPLC (Waters, Milford, Mass.) using a linear gradient of increasing mobile phase (acetonitrile 10 to 90% in water with 0.1% TFA) and a Waters)(Bridge BEH 130 C18 column (4.6×100 mm, particle size 5 μm). Absorbance at 215 nm was utilized as the monitoring wavelength, though 260 and 280 nm were also collected. LC spectra were analyzed with MassLynx Software v.4.1 (Waters). Matrix-assisted laser desorption ionization (MALDI) mass spectroscopy was utilized to confirm correct peptide mass (Voyager System 4291, Applied Biosystems) (Anderson et al. (2008) Biotechnol Lett., 30: 813-818).
MIC Assay
Peptides were evaluated for basic antimicrobial activity by broth microdilution, as described previously (Eckert et al. (2006) Antimicrob Agents Chemother., 50: 3651-3657; Eckert et al. (2006) Antimicrob Agents Chemother., 50: 1480-1488). Briefly, ˜1×105 cfu/mL bacteria were diluted in TH ( S. mutans ), or Mueller-Hinton (MH) broth (all other organisms) and distributed to 96-well plates. Serially-diluted (2-fold) peptides were then added and the plates incubated at 37° C. for 18-24 h. Peptide MIC was determined as the concentration of peptide that completely inhibited organism growth when examined by eye (clear well). All experiments were conducted 10 times.
Post-Antibiotic Effect Assay
The activity and selectivity of MH-STAMPs after a 10 min incubation was determined by growth retardation experiments against targeted and untargeted bacteria in monocultures, as described previously (Id.). Cells from overnight cultures were diluted to ˜5×106 cfu/mL in MH (or TH with 1% sucrose for S. mutans ), normalized by OD600 0.05-0.1 and seeded to 96-well plates. Cultures were then grown under the appropriate conditions for 2 h (3 h for S. mutans ) prior to the addition of peptides for 10 min. Plates were then centrifuged at 3000×g for 5 min, the supernatants discarded, fresh medium returned (MH or TH without sucrose for S. mutans ), and incubation resumed. Bacterial growth after treatment was then monitored over time by OD600.
Microbial Population Shift Assay
Mixed planktonic populations of P. aeruginosa, E. coli, S. epidermidis , and S. mutans were utilized to examine the potential of MH-STAMPs to direct species composition within a culture after treatment. Samples were prepared containing: ˜6×10 4 cfu/mL S. mutans, ˜ 2×10 4 cfu/mL E. coli, ˜ 2×104 cfu/mL S. epidermidis , and ˜0.5×10 4 cfu/mL P. aeruginosa in BHI (mixed immediately before peptide addition). Peptide (10 μM) or mock-treatment (1×PBS) was then added and samples were incubated at 37° C. for 24 h under anaerobic conditions (80% N 2 , 15% CO 2 , 5% H 2 ). After incubation, samples were serially diluted (1:10) in 1×PBS and aliquots from each dilution were then spotted to agar plates selective for each species in the mixture: TH plus 800 μg/mL spectinomycin ( S. mutans ), LB plus 25 μg/mL ampicillin ( P. aeruginosa ), LB plus 200 μg/mL spectinomycin ( E. coli ), and mannitol salt agar (MSA, S. epidermidis ) in order to quantitate survivors from each species. Plates were then incubated 37° C. under aerobic conditions (TH plates were incubated anaerobically) and colonies counted after 24 h to determine survivors. Expected colony morphologies were observed for each species when plated on selective media. Gram stains and direct microscopic observation (from select isolated colonies) were undertaken to confirm species identity (data not shown). The detection limit of the assay was 200 cfu/mL.
Results
Design and Synthesis of Multi-Headed STAMPs
We constructed a prototype MH-STAMP from the well-established targeting peptides KH (specific to Pseudomonas spp) and M8 (specific for Streptococcus mutans ). The wide-spectrum antimicrobial peptide BD2.20 was utilized as the base AMP for all MH171 STAMP construction. BD2.20 is a novel synthetic AMP with a cationic and amphipathic residue arrangement, which has robust MICs against a variety of Gram-negative and Gram-positive organisms (Table 19). For the synthesis of MH-STMAP M8(KH)-20 (construct presented in FIG. 15 ), BD2.20 and a Lys (Mtt-protected side-chain) residue were joined via an activated alkane spacer, followed by addition of the M8 targeting peptide to the N-terminus of the product. Selective deprotection of the central Lys(Mtt) side chain was then undertaken and the KH targeting peptide attached. The correct molecular mass (4888.79) and ˜90% purity was confirmed by HPLC and MALDI mass spectrometry ( FIG. 16 ).
The non-binding “blank” targeting peptide BL-1 was incorporated into the synthesis scheme in place of KH or M8 to construct variant MH-STAMPs possessing a single functional targeting head: M8(BL)-20 and BL(KH)-20. The correct MW and acceptable purity were observed for these MH-STAMPs ( FIG. 15 , data not shown).
General Antimicrobial Activity of Multi-Head Constructs
After synthesis, the completed MH-STAMPs were evaluated for general antimicrobial activity by MIC against a panel of bacteria. As shown in Table 19, the MH-STAMP constructs M8(KH)-20, BL(KH)-20, and M8(BL)-20 were found to have similar activity profiles to that of BD2.20 for the organisms examined (less than two titration steps in 10-fold difference). Additionally, we observed a difference in general susceptibility between P. aeruginosa and the other organisms tested, suggesting this bacterium is more resistant to BD2.20. Overall, these data indicate that the addition of the targeting domains to the base sequence was tolerated and did not completely inhibit the activity of the antimicrobial peptide.
Peptide selectivity could not be determined utilizing these methods, as STAMPs and their parent AMP molecules often display similar MICs, but have radically different antimicrobial kinetics and selectivity due to increased specific-killing mediated by the targeting regions (Id.). Therefore, we performed different experiments to test for antimicrobial selectivity and functional MH-STAMP construction.
Selectivity and Post-Antibiotic Effect of MH-STAMP Constructs
MH-STAMP antimicrobial kinetics was ascertained utilizing a variation of the classical post-antibiotic effect assay, which measures the ability of an agent to affect an organism's growth after a short exposure period. Monocultures of WI-STAMP-targeted and untargeted organisms were exposed to M8(KH)-20, M8(BL)-20, BL(KH)-20, or unmodified BD2.20, then allowed to recover. As shown in FIG. 17A , S. mutans growth was effectively retarded by M8-containing constructs (M8(KH)-20, M8(BL)-20), but was not altered by a MH-STAMP construct lacking this region (BL(KH)-20). Similarly, the growth of the other targeted bacterium, P. aeruginosa , was inhibited in a KH-dependant manner ( FIG. 17B ). In comparison, the non-targeted bacteria E. coli, S. aureus , and S. epidermidis were not inhibited by treatment with any MH-STAMP and were only inhibited by the base antimicrobial peptide BD2.20, which displayed robust antimicrobial activity against all examined strains. These results indicate that MH-STAMPs containing KH or M8 targeting domains have activity against P. aeruginosa or S. mutans , respectively, and not other bacteria. Furthermore, replacement of the targeting region with a non-binding peptide abolishes specific activity.
Ability of MH-STAMPs to Direct a “Population Shift” within a Mixed Species Population
We hypothesized that potential MH-STAMP dual-functionality could affect a particular set of bacteria within a mixed population, thereby promoting the outgrowth of non-targeted organisms and “shifting” the constituent makeup. To examine this possibility, defined mixed populations of planktonic cells were treated continuously and the make-up of the community examined after 24 h. As shown in FIG. 18 , treatment with the wide spectrum AMP BD2.20 resulted in a significant loss of recoverable cfu/mL after 24 h from all species in the mixture. Treatment with M8(KH)-20 was found to alter this pattern; we observed ˜1×10 5 cfu/mL surviving E. coli and S. epidermidis , but did not recover S. mutans or P. aeruginosa cfu/mL. In BL(KH)-20 treated samples, P. aeruginosa cfu/mL were not observed, though we recovered higher than input cfu/mL from S. mutans and unchanged numbers of S. epidermidis and E. coli . In samples exposed to M8(BL)-20, S. mutans recoverable cfu/mL were greatly reduced compared to input cfu/mL, while other species were not affected or affected to a lesser extent. Interestingly, these results suggest that M8(KH)-20, M8(BL)-20, and BL(KH)-20 retain their ability to affect organisms recognized by the targeting regions present, even within a mixed population of bacteria.
Discussion
Our results indicate that we have successfully constructed a STAMP with dual antimicrobial specificities controlled by the targeting peptides present in the molecule; KH for Pseudomonas spp, M8 for S. mutans . In a closed multi-species system ( FIG. 18 ), the dual specificity of M8(KH)-20 was readily discernable: the population of the culture “shifted” away from targeted organisms after MH-STAMP treatment. The targeted bacteria were eliminated and the population of untargeted organisms increased, to varying degrees, above-input cfu/mL. Additionally, interruption of KH or M8 in the MH-STAMP construct with the non-binding peptide BL-1 resulted in the expected elimination of only one targeted species. These results support the hypothesis that functional MH-STAMPs could be constructed from a wide-spectrum AMP base.
The emergence of metagenomics and the development of more sensitive molecular diagnostics has driven an increase in the understanding of human-associated microbial ecologies and host-microbe interactions (Aas et al. (2005) J Clin Microbiol., 43: 5721-5732; Boman (2000) Immunol Rev., 173: 5-16; Kreth et al. (2005) J Bacteria, 187: 7193-7203). At mucosal surfaces, it has become clear that our bodies harbor an abundance of residential flora which may impact innate and humoral immunity, nutrient availability, protection against pathogens, and even host physiology (Metges (2000) J Nutr., 130: 1857S-64; Sears (2005) Anaerobe, 11: 247-251; Lievin-Le et al. (2006) Clin Microbiol Rev., 19: 315-337; DiBaise et al. (2008) Mayo Clinic Proceedings 83: 460-469). Furthermore, findings have indicated that shifts in the diversity of normal flora are associated with negative clinical consequences; for example the overgrowth of S. mutans in the oral cavity during cariogenesis (linked to the uptake of sucrose) or the antibiotic-assisted colonization of the intestine by Clostridium difficle (Loesche (1986) Microbiol Rev., 50: 353-380; Gould and McDonald (2998) Crit Care 12: 203). Other population shifts may be linked to axilla odor ( Corynebacteria spp) (Leyden et al. (1981) J Invest Dermatol., 77: 413-416; Elsner (2006) Curr Probl Dermatol., 33: 35-41), or even host obesity. Given the quantity and diversity of microbes present, pathogenesis at mucosal surfaces is not likely to be associated with the overgrowth of a single strain or species. More often, it is a population shift resulting in the predominance of two or more species; for example the persistence of Burkholderia cepacia and P. aeruginosa in cystic fibrosis airway or Treponema denticola and Porphymonas gingivalis and other “red cluster” organisms in gingivitis (Govan and Deretic (1996) Microbiol Rev., 60: 539-574; Paster et al. (2001) J Bacteriol., 183: 3770-3783). In many cases (such as the latter) these species may have only distant phylogenetic relationships and display differential susceptibilities to antibiotic therapies resulting in persistent disease progression despite treatment (Schlessinger (1988) Clin Microbiol Rev., 1: 54-59; Tresse et al. (1997) J Antimicrob Chemother., 40: 419-421). Currently, available treatments for infections of mucosal surfaces are largely non-specific (traditional small-molecule antibiotics, mechanical removal), and thus are not effective in retaining flora or shifting the constituent balance back to a health-associated composition (Keene and Shklair (1974) J Dent Res., 53: 1295). There is a need for a therapeutic treatment that can selectively target multiple pathogens, regardless of their phylogenetic relationship, and MH-STAMPs can help achieve this goal.
In monoculture experiments ( FIG. 17 ), our results suggest that M8 or KH inclusion in the MH-STAMP drove activity towards S. mutans or P. aeruginosa , but also that the presence of a targeting domain reduced the activity of the parent AMP BD2.20 against untargeted organisms. In contrast, the results of our MIC assays (Table 19) indicate little difference in activity between BD2.20 and any MH-STAMP. Against untargeted organisms, the M8 and KH regions are likely to have a negative, but not completely inhibitory, impact on BD2.20 activity. Given the long duration of activity and the lower inoculum size in the MIC assay (compared with experiments in FIG. 17 ), it is likely that all BD2.20-containing peptides could reach equal levels of growth inhibition, despite large and target-specific differences in antimicrobial speed. This pattern of results was also observed when comparing MICs of targeted and untargeted organisms utilizing STAMPs against S. mutans and Pseudomonas mendocina (Eckert et al. (2006) Antimicrob Agents Chemother., 50: 3651-3657; Eckert et al. (2006) Antimicrob Agents Chemother., 50: 1480-1488).
Although more rigorous studies and a more medically relevant combination of pathogen targets is desirable, these findings indicate that it is possible to design an antimicrobial peptide-based therapeutic with multiple and defined fidelities in vitro. MH-STAMPs may help improve human health through the promotion of healthy microbial constituencies.
Example 2
Synthesis of Peptide—Porphyrin Conjugate
The mixture of coupling reagent HATU (5 eq. excess, 10 mg) and purpurin-18 (MW 564, 5 eq excess, 15 mg) in 600 mL dry dichloromethane (DCM):DMF:dimethylsulphoxide (DMSO) (1:1:1 (v/v)) was added to the peptide resin (1 molar equivalent, 15 mg) which was swelled by placing in minimal DMF for 30 min prior to reaction. 26 μL (10 molar equivalents) DIPEA was then added to the reaction flask to initiate the reaction. The reaction mixture was protected with argon and stirred at room temperature for 3 h.
After finishing, the reaction mixture was then passed down a sintered glass filtered vial and extensively washed with DMF and DCM to remove all waste reagents. The resin was then dried overnight in vacuum, and cleaved with 1 ml of trifluoroacetic acid (TFA)/thioanisole/water/EDT (10/0.5/0.5/025) for 2 hr at room temperature, and the cleavage solution was precipitated with 10 mL methyl-tert butyl ether. The precipitate was washed twice with the same amount of ether.
Example 3
Synthesis of Peptide—CSA Conjugate
To the fully protected peptide (solution of B43-GGG (FIDSFIRSF-GGG, 0.025 mmol) and tri-Boc-CSA-15 (0.0125 mol) in 300 μL DMF, DCC (7.7 mg), HOBt (5.1 mg) and 13 μL DIEA were added in iced-bath. After stirred at room temperature for four days, the reaction mixture was poured into 5 ml water and extracted with chloroform (5×3 mL). The CHCl 3 extract was evaporated under vacuum and dried in a lyophilizer overnight. The dried CHCl 3 extracts was then dissolved in 1 mL DCM followed by added 1 mL of TFA in iced-bath. The reaction mixture was further stirred at room temperature for 2 hours and precipitated with methyl tert-butyl ether (10 mL). The precipitate was further washed once with the same amount ether and dried in vacuum.
Example 4
STAMPs Against Corynebacterium jeikeium and Streptococcus mutans
This example illustrates the development of STAMPs to selectively target and reduce or eliminate Streptococcus mutans (dental caries) or Corynebacterium jeikeium (body odor, opportunistic infections) from mixed microbial populations.
Axilla odor is caused by overgrowth of, and metabolite production from, Corynebacterium spp, which replaces Staphylococcus and Micrococcus spp associated with less odor. Current hygiene (soaps, antibiotics, antiseptics, disinfectants) practices remove all bacteria, allowing the ratio of Corynebacteria to normal flora to remain high during regrowth. Deodorants and anti-perspirants are temporary solutions that hide or even exacerbate the problem.
S. mutans is the major etiological agent of dental caries. Current methods (tooth brushing, antiseptic mouthrinses) to treat cariogenesis have focused on complete bacterial removal, i.e., elimination of S. mutans and other harmless oral bacteria. Caries have persisted despite these methods, and in many cases, S. mutans can become the dominant organism in the mouth. Several S. mutans and acid-targeted approaches (probiotic replacement, saliva pH adjustment) are under development, but none have shown clinical efficacy.
This example describes a number of STAMPs that preferentially or selectively reduce or eliminate S. mutans and/or Corynebacterium spp from mixed populations.
Several lead STAMPs with specific activity against Corynebacterium jeikeium are also disclosed herein.
The STAMPs described herein comprise functional regions within a peptide molecule or a chemical conjugate. These regions include a targeting region comprising one or more targeting moieties (e.g., targeting peptides), a linker, and one or more killing moieties (e.g., antimicrobial peptides (AMPs), porphyrins, etc.).
The STAMPs function through the targeting region, which selectively accumulates STAMPs, and therefore killing regions, on or in proximity to the microorganism of interest. Other flora are not recognized by the targeting region, and therefore avoid or have reduced STAMP accumulation and cellular damage.
In certain embodiments, STAMPs against oral S. mutans are best applied formulated in a mouthrinse, toothpaste, cream, gel, or adhesive strip, and in certain preferably embodiments, are provided in a formulation that comprises 0.5 to 2.5×PBS (or other salt) and other ingredients commonly found in oral healthcare formulations (e.g., mouthrinse formulations). Certain illustrative formulations are shown in Table 20.
During the course of evaluating STAMPs, antimicrobial peptides (AMPs), and binding peptides for desired activity, it was discovered that certain formulations can attenuate or promote peptide activity, as compared to activity levels in a default buffer system (1×PBS). In some cases, 1×PBS may provide the best level of activity. Below are a number of formulations that alter, or may alter, peptide or STAMP activity. For complex buffer systems, assume the base solvent is water unless otherwise stated.
Formulation 1 (1×PBS, pH 7.4): 136.8 mM NaCl, 2.68 mM KCl, 1.01 mM Na 2 HPO 4 , and 1.37 mM KH 2 PO 4 .
Formulation 2 (HEPES/CTAB): 20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 150 mM NaCl, 1 mM MgCl 2 , and 0.1% CTAB (Cetyl trimethylammonium bromide).
Formulation 3 (TRIS/CTAB): 20 mM Tris (tris(hydroxymethyl)aminomethane), pH 7.5, 150 mM NaCl, 1 mM MgCl 2 , and 0.1% CTAB.
Formulation 4: 20 mM HEPES.
Formulation 5: 20 mM Tris, pH 7.5.
Formulation 6: 0.2% CTAB.
Formulation 7: 1% Glycerol.
Formulation 8: 1% Pluronic F108 (nonionic surfactant: α-Hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymer).
Formulation 9: 1% Pluronic F123 (Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), average M n ˜5,800).
Formulation 10: 1% Pluronic F17R4 (Poly(propylene glycol)-block-poly(ethylene glycol)-block-poly(propylene glycol), average M n ˜2,700).
Formulation 11: 1% to 7% PEG400.
Formulation 12: 50 mM Urea.
Formulation 13: 10 mM AOT (Sodium bis(2-ethylhexyl) sulfosuccinate).
Formulation 14: 0.5-0.1% Tween 20 (nonionic detergent, also known as polysorbate 20 or PEG(20)sorbitan monolauratesorbitan monolaurate).
Formulation 15: 0.5-0.1% Tween 80 (nonionic surfactant, C 64 H 124 O 26 , also known as polyoxyethylene (20) sorbitan monooleate, (x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl), or POE (20) sorbitan monooleate).
Formulation 16: 5-10% Ethanol.
Formulation 17: 20% Glycerin.
Formulation 18: 20% Sorbitol.
Formulation 19: 10% Glycerin/10% Sorbitol.
Formulation 20: 0.1% SLS (Sodium lauryl sulfate).
Formulation 21: 1% Pluronic F127 (nonionic surfactant: α-Hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymer).
Formulation 21: 0.1% Tween 20 (nonionic detergent, also known as Polysorbate 20, or PEG(20)sorbitan monolaurate).
Formulation 21: 10% PG (phospholipid gel).
Mouthrinse neat solution #1 (made in 1×PBS): 7% ETOH, 20% Glycerin, 7% PEG 400, and 1% PLURONIC® F127.
Mouthrinse neat solution #2 (made in 1×PBS): 7% ETOH, 20% Sorbitol, 7% PEG 400, and 1% PLURONIC® F127.
Mouthrinse neat solution #3 (made in 1×PBS): 7% ETOH, 20% Glycerin and 7% PEG 400.
Mouthrinse neat solution #4 (made in 1×PBS): 7% ETOH, 20% Sorbitol and 7% PEG 400.
Other illustrative, but not limiting, mouthrinse formulations are shown in Table 20.





TABLE 20



Illustrative mouthrinse formulations.









Rinse#
ETOH
Glycerin
PEG400
F127
Water 1
Fluoride











1
5
22.5
7
1
64.5
187.5

2
6
25
1
0
68
0

3
6
20
7
0
67
0

4
6
20
1
1
72
0

5
7
25
7
0
61
0

6
7
20
1
0
72
0

7
7
20
7
0
66
250

8
5
20
7
1
67
0

9
6.472
21.139
5.361
0.722
66.306
250

10
7
22.5
1
0
69.5
250

11
5
25
1
0
69
250

12
7
20
7
0
66
250

13
5
20
1
1
73
250

14
5
25
7
0.5
62.5
250

15
7
25
1
0.5
66.5
250

16
7
25
7
1
60
250

17
5
25
7
0.5
62.5
0

18
7
20
1
1
71
250

19
6
25
1
1
67
250

20
7
25
7
1
60
125

21
5
25
1
0
69
250

22
5
20
1.5
0.5
73
0

23
7
20
1
1
71
250

24
6
20
1
0
73
250

25
5
22.333
3.778
0.444
68.444
125

26
7
25
1
1
66
0

27
6
25
7
0
62
250

28
7
20
7
1
65
0

29
7
25
4
1
63
62.5

30
5
25
4
0
66
0

31
5
25
1
1
68
0

32
7
25
7
1
60
0

33
7
22.5
4
0.5
66
0

34
5
20
4.5
0
70.5
250

35
5
23
1
0
71
62.5

36
6
20
1
1
72
0

37
5
20
7
1
67
250

38
7
20
1
0
72
0

39
5
25
4
1
65
250

40
5
22.5
7
0
65.5
0

n1
7
20
7
1
65
0

n2
7
20%
7
1
65
0



Sorbitol

n3
7
20
7
0
66
0

n4
7
20%
7
0
66
0



Sorbitol



1 1xPBS can be substituted for water




































































In certain embodiments, Corynebacterium -specific STAMPs are formulated in any number of creams, nanoemulsions, lipid micelles, aqueous or no-aqueous gels, sprays, soaps or roll-on bars, or other products used for axilla or other hygiene.
STAMP-mediated selective antimicrobial activity can result in preservation of the normal flora at the oral or axilla mucosal surface, resulting in protective colonization and the conversion of a harmful flora to a beneficial one. Recurrence of pathogen overgrowth would be reduced, which also limits the amount and frequency (and therefore cost) of STAMP delivery. STAMPs allow for “surgical” antimicrobial precision, which limits antimicrobial resistance evolution as well due to the general mechanism of cell membrane damage mediated by the killing region.
A number of anti- S. mutans STAMPs (see Table 21) and anti- C. jeikeium STAMPs have been designed and tested, some in formulations. All show potent selective activity against their bacterial targets in vitro, including against biofilm forms. When tested, STAMPs have little cytotoxicity against cell lines in vitro.





TABLE 21



Illustrative anti- S. mutans STAMPs. Single underline is

binding peptide. Double underline is antimicrobial

peptide (AMP). No underline is linker. *indicates

optionally protected (e.g., amidated) C terminal.





STAMP
Amino Acid Sequence
SEQ ID NO



2_1G2
FIKHFIHRF GGG KNLRIIRKGIHIIKKY *
3230



C16AF5
TFFRLFNRSFTQALGK GGG FLKFLKKFFKKLKY *
3231



1845L621
KFINGVLSQFVLERK PYP KLFKFLRKHLL *
3232



1903-21
NIFEYFLE GGG KLFKFLRKHLL *
3233



































TABLE 22



Illustrative anti- C. jeikeium STAMPs. Single underline is

binding peptide. Double underline is antimicrobial peptide

(AMP). No underline is linker. *indicates optionally protected

(e.g., amidated) C terminal.





STAMP
Amino Acid Sequence
SEQ ID NO



2038L6CAM
GKAKPYQVRQVLRAVDKLETRRKKGGR PYP GWR
3234

135
LIKKILRVFKGL *




1619-
SKRGRKRKDRRKKKANHGKRPNS GGG GWRLIKKI
3235

CAM135
LRVFKGL *




1599-BD2.16
YSKTLHFADGGG KILKFLFKKVF *
3236



1619-BD2.16
SKRGRKRKDRRKKKANHGKRPNS GGG KILKFLFK
3237


KVF *




1904-BD2.16
GSVIKKRRKRMSKKKHRKMLRRTRVQRRKLGKG
3238


GG KILKFLFKKVF *




































It was a surprising discovery that certain anti- S. mutans STAMPs required a salt in the formulation (e.g., PBS) for optimum activity. Thus, for example, the anti- S. mutans STAMP C16G2 (TFFRLFNRSFTQALGKGGGKNLRIIRKGIHIIKKY*, SEQ ID NO:2) comprising the TFFRLFNRSFTQALGK (SEQ ID NO:1) attached to the antimicrobial peptide (AMP) KNLRIIRKGIHIIKKY (SEQ ID NO: 3080) by a peptide linker (GGG) was substantially inactive in water-based salt-free buffers and nanoemulsions, but was active in a phosphate buffered saline (PBS) formulation. Suitable PBS formulations ranged from 0.5×PBS to about 2.5×PBS with an activity optimum at about 1×PBS. Similar results are believed to obtain for other anti- S. mutans STAMPS as well as a number of other STAMPs. In certain embodiments STAMP stability in solution was improved by inclusion of fluoride in mouthrinse.
Example 5
Photodynamic Therapy Targeted Against Streptococcus mutans
Dental caries (tooth decay) is one of the most prevalent and costly infectious diseases in the United States. Currently, the annual expenditures on dental services exceed $85 billion, with the majority of these costs attributable to dental caries and its sequelae (www.ada.org/). The oral cavity harbors a complex microbial community consisting of over 600 different non-harmful/commensal microbial species together with a limited number of pathogenic bacteria, including the major etiological agent of dental caries, Streptococcus mutans . Once established, S. mutans generates acid during the fermentation of dietary sugars, which causes the demineralization of tooth structure and inhibits the growth of non-pathogenic commensal bacteria within the same microbial niche. Despite diligent use of broad-spectrum antimicrobial compounds and tooth brushing, S. mutans persists within the oral cavity and causes repeated cycles of cariogenesis. Current “remove all, kill-all” approaches have shown limited efficacy, since a “cleaned” tooth surface provides an equal opportunity for commensal as well as pathogenic bacteria to re-colonize in the non-sterile environment of the oral cavity. To address this shortcoming, we have constructed and evaluated a light-activated S. mutans -selective antimicrobial agent. C16-RB, constructed via conjugation of the S. mutans competence-stimulating peptide to the photodynamic dye rose bengal, displays robust anti- S. mutans activity in vitro under blue exposure from a handheld dental curing light. C16-RB has reduced activity against other oral streptococci under mixed biofilm conditions and has limited cytotoxicity in vitro.
To develop a method of selectively eliminating S. mutans from a dental biofilm so that beneficial species exert a protective colonization effect and long-term protection from S. mutans re-colonization can be attained we created a novel class of targeted antimicrobials, known as specifically-targeted antimicrobial peptides, or STAMPs. STAMPs consist of functionally independent, yet conjoined, domains within a linear peptide sequence; a targeting region and an antimicrobial region. The targeting region, which binds specifically to a bacterial species of interest, delivers the killing portion of the molecule that consists of a normally wide-spectrum antimicrobial peptide. Previously, we successfully designed STAMPs against S. mutans by taking advantage of the competence stimulating pheromone (CSP) peptide produced by this organism that has demonstrated S. mutans -specific recognition. STAMPs synthesized with portions of CSP as targeting domains were capable of specific antimicrobial activity against S. mutans , and not other oral streptococci or non-cariogenic organisms in biofilms.
We hypothesized that targeted killing might be achieved through the use of non-peptide antimicrobial molecules, such as porphyrins or dyes utilized in PDT. Here we present the proof-of-principle construction and in vitro efficacy of the targeted, peptide-guided, photodynamic molecule C16-RB. C16-RB displays S. mutans selective antimicrobial activity upon blue light activation with limited activity against non-cariogenic oral streptococci and epithelial cells.
Materials and Methods
Synthesis of C16-RB
All amino acids, synthesis resins and reagents were peptide synthesis grade (Anaspec, San Jose, Calif.; Fisher Scientific). To construct our C16-RB conjugate, conventional 9-fluorenylmethoxy carbonyl (Fmoc) solid-phase methodology was employed to synthesize the CSP C16 peptide and attach the succinate and PEG linkers, utilizing double coupling cycles in N-hdroxybenzotrazole, HBTU (O-benzotriazole-N,N,N,N-tetramethyl-uronium hexafluoro-phosphate) and diisopropyl ethylamine (DIEA), with dimethylformamide (DMF) and N-methylpyrrolidone (NMP) as solvents, as described previously. The peptide resin (1 molar equivalent, 15 mg) was then swollen in DMF for 30 min prior to attachment of the PEG terminal amide group to the carboxyl lactone in RB ( FIG. 19B ). This reaction was carried out in a mixture of 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 5-molar excess) in dichloromethane (DCM):DMF:dimethylsulphoxide (DMSO) (1:1:1 (v/v)). Ten molar equivalents of DIEA were added to the reaction flask to initiate the reaction, which was protected with argon and stirred at room temperature for 5 h. After completion, the reaction mixture was passed down sintered glass filtered vial and extensively washed with DMF and DCM to remove all waste reagents. The resin was then dried overnight in vacuum, and cleaved with 1 mL of trifluoroacetic acid (TFA)/thioanisole/water/EDT (10/0.5/0.5/025) for 2 hr at room temperature. The cleavage solution was precipitated with 10 mL methyl-tert butyl ether, and the precipitate was washed twice with the same amount of ether. The crude product was purified via preparative-level HPLC (Source 15RPC column, ACTA purifier, Amersham) and eluted with gradient acetonitrile/water from 10 to 35% in 10 min, which was increased to 90% over 8 min before finally being washed 15 min with 95% acetonitrile.
C16-RB was purified further to >90% and the molecular mass confirmed via LC/MS, utilizing increasing hydrophobicity gradient of acetonitrile in water with 0.01% TFA as described above (Waters X-bridge BEH 130 C18 column, 4.6×100 mm, particle size 5 μm, Waters 3100 system). LC spectra were analyzed with MassLynx Softward v. 4.1 (Waters). C16-RB mass (3118.0) was confirmed by electrospray ionization (ESI) mass spectroscopy in linear, positive ion mode. The final product was lyophilized and protected from light at all times. C16-RB was soluble in 50% methanol.
Bacterial and Cellular Growth
Streptococcus oralis ATCC 10557, Streptococcus gordonii (Challis), Streptococcus sanguinis (NY101), Streptococcus mitis ATCC 903, Streptococcus salivarius ATCC 13419 and S. mutans wild-type UA140 and JM11 (spectinomycin-resistant) strains were grown in Todd-Hewitt (TH) broth 37° C. in an anaerobic atmosphere of 80% N 2 , 10% CO 2 , and 10% H 2 . BHK-21 (ATCC CRL-10) fibroblasts were propagated in DMEM with 10% FBS, 1 mM sodium pyruvate, 100 units/mL penicillin G, and 100 μg/mL streptomycin at 37° C. with 5% CO 2 . Cells were detached with 0.25% trypsin and subcultured as recommended by the supplier.
Photodynamic Antimicrobial Assays Against Biofilms
To evaluate C16-RB against monoculture biofilms, S. mutans UA140 was grown overnight in TH prior to inoculation for biofilm formation. For biofilms, 1:5000 dilution of overnight culture was made into TH with 1% sucrose in 2 mL centrifuge tubes (200 μL volume) and grown 24 h under anaerobic conditions. After incubation, biofilms were treated for 5 min with 5 or 25 μM C16-RB or 5 μM RB in 1×PBS, or PBS alone, followed by removal of supernatant and exposure to 5 min blue light (emission 400-550 nm, power 400 mW/cm 2 ) from an Astralis 7 (Ivoclar Vivodent, Austria) handheld LED commonly used as a dental curing light. The light source was suspended 4 cm from the tube bottom (even with the mouth of the tube). A duplicate set of samples were left covered to serve as dark controls. After treatment, biofilms were mechanically disrupted and plated to determine cfu/mL.
To gauge C16-RB selectivity for S. mutans , similar assays were conducted against multispecies biofilms. Mixed biofilms were seeded by diluting (1:5000) a mixture of equal parts S. oralis, S. gordonii, S. mitis, S. sanguinis, S. salivarius , and S. mutans JM11 (made from overnight cultures) into TH with 1% sucrose, 1% glucose, and 1% mannose. Biofilms were incubated and treated as described above with the addition of vitamin C or potassium gluconate. After the addition of agent and 5 min incubation, biofilms were washed 1× with 1×PBS prior to light exposure. After PDT and biofilm disruption, survivors were plated on TH, and TH supplemented with 800 μg/mL spectinomycin, which allowed for quantitation of surviving total oral streptococci and surviving S. mutans , respectively.
Evaluation of C16-RB Cytotoxicity
The effect of RB and C16-RB on human fibroblasts was ascertained by utilizing the Promega CellTiterGlo assay, as described by the manufacturer. Briefly, fibroblasts were grown to confluence, detached, and seeded to ˜5,000 cells per well in a 96-well opaque walled, clear bottom 96-well plate (Nunc International). For long-term dark toxicity, cells were allowed to attach to for 18 h before the culture medium was replaced with medium plus serially-diluted RB or C16-RB (200 μM to 390 nM) or medium alone. After 18-24 h, equal volume Cell Titer Glo reagent was added to each well and mixed. Luciferace activity was then quantified to measure cell viability (Varian Fluorometer in Biolumenescence mode). To measure cytotoxicity after RB or C16-RB light exposure, cells were seeded at ˜10,000 cells per well and allowed to attach for 4 h. Cell growth medium was then replaced with RB or C16-RB containing medium, prior to exposure (a single well at a time) with blue light (400 mW/cm 2 ) suspended ˜3 cm from the well bottom. After exposure, cultures were disrupted with Cell Titer Glo and luciferase activity quantitated as above.
Results
Design of Photodynamic Peptide-Dye Conjugate
For the targeting peptide component of the chimeric molecule, we selected a shortened derivative of S. mutans CSP, CSP C16 (sequence: TFFRLFNRSFTQALGK). CSP C16 has been utilized successfully as a STAMP targeting peptide in several constructs, and demonstrates selective binding to S. mutans and not other non-cariogenic bacteria. For the photodynamic dye, we selected rose bengal (RB, FIG. 19A ), a xanthene dye with a demonstrated record of safety as a diagnostic tool in optometry. Unlike TBO or methylene blue, RB is not recognized by efflux pumps, and has shown robust activity against a variety of bacteria in vitro in the presence of green or blue light (max absorption ˜549 nm), and can be activated by a handheld dental curing LED.
C16-RB Synthesis
As shown in FIG. 19B , RB was attached to the N-terminus of CSP C16 through a succinate/PEG linker to construct the C16-RB molecule. Conventional solid-phase peptide methods were utilized to synthesize CSP C16 , followed by linker and RB coupling prior to cleavage from the resin. After cleavage, C16-RB was repeatedly purified by LC/MS prior to evaluation. As shown in FIG. 20 , over 95% purity was achieved with the expected mass species observed. The lactone ring in RB was opened as a result of CSP C16 attachment. However, we hypothesized that the conjugate would retain enough singlet-oxygen generating activity for a proof-of-principle demonstration, as other xanthene dyes with activity lack this ring.
C16-RB Efficacy Against Single-Species S. mutans Biofilms
After synthesis, the basic photosensitization potential of C16-RB was assessed by challenging mature single-species S. mutans biofilms (grown 24 h) with C16-RB or unmodified RB, followed by blue emission from a dental curing light. As shown in FIG. 21 , potent antimicrobial activity was observed in cultures exposed to C16-RB or RB and blue light: a reduction in over 3 log in from input cfu/mL at 5 or 25 μM In contrast, appreciable decreases in cfu/mL were not observed in S. mutans treated with blue light alone, or 5 μM RB or C16-RB dark controls. Modest dark toxicity was observed in samples treated with 25 μM C16-RB. Overall, these results indicate that the peptide-dye conjugate is active against S. mutans and at roughly similar levels to the parental RB molecule.
Selective PDT Against Multi-Species Biofilms
C16-RB was next evaluated for selectivity in mixed cultures containing S. mutans and non-cariogenic oral streptococci that compete for the same niche on the tooth surface. We utilized mixed biofilms of S. mutans transformed with spectinomycin resistance (strain JM11, Merritt, et al., 2005), plus S. oralis, S. gordonii, S. mitis, S. sanguinis , and S. salivarius . The mixed cultures were grown 24 and then treated with RB or C16-RB as indicated, plus potassium gluconate to minimize killing of untargeted bacteria by reducing the superoxide-producing activity of the free C16-RB not bound to S. mutans . Ethanol treatment served as an indiscriminant killing control. As shown in FIG. 21 , RB alone exhibited strong indiscriminant photodynamic antimicrobial effects against S. mutans and non- S. mutans in the mixed biofilm system (ratio of surviving S. mutans :non-cariogenic streptococci cfu ˜1). In contrast, C16-RB displayed specific photodynamic activity towards S. mutans , and not the other oral streptococci examined, as reflected in the low ratio of recovered S. mutans to other streptococci. These results suggest C16-RB has antimicrobial activity in the presence of blue light that is specific for S. mutans and dependent on the CSP C16 targeting peptide.
Cytotoxicity Against Eukaryotic Cells
Given the demonstrated PDT potential of RB-C16, experiments were conducted to examine the cytotoxicity for this conjugate and RB alone. IC 50 s were obtained for BHK cells exposed C16-RB, RB, or Melittin B (positive control for cytotoxicity), with and without blue light exposure. As shown in Table 23, cytotoxicity was noted for cells exposed to Melittin B at the lowest peptide dilution tested at either 5 min or 24 h, with or without light (IC 50 <1.56 while light-dependent toxicity was observed only for RB-treated samples. No photo-associated toxicity was noted in BHK cells treated with C16-RB, though modest light-independent cytotoxicity (IC 50 =90 μM) was detected after 24 h of exposure. These results suggest that C16-RB is not toxic to BHK cells after illumination, and displays mild toxic effects (when compared to Melittin B) after 24 h exposure.





TABLE 23



Cytotoxicity of RB and C16-RB compounds.





IC 50 (μM)


BHK









5 min dark:



RB-C16
>100


RB
>100


Melittin B
<1.56


5 min w/blue light:


RB-C16
>100


RB
40


Melittin B
<1.56


24 h dark


RB-C16
55


RB
90


Melittin B
<1.56





































It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.