US008389679B2

(12) United States Patent (10) Patent No.: US 8,389,679 B2 Eckert et al. (45) Date of Patent: Mar. 5, 2013

(54) TARGETED ANTIMICROBIAL MOIETIES 2007/011 1251 A1* 5/2007 Rosania et al...... 435/71 2008. O170991 A1* 7, 2008 Shi et al...... 424,169 2011 OO39761 A1* 2, 2011 Eckert et al. ... 514/24 (75) Inventors: Rat d ES Int Ph CA 2011/026,2508 A1* 10, 2011 Watt et al...... 424/405 (US); Daniel Yarbrough, Los Angeles, 2012,0003661 A1 1/2012 Eckert et al...... 435/6.15 CA (US); Wenyuan Shi, Los Angeles, CA (US); Maxwell Anderson, Sequim, FOREIGN PATENT DOCUMENTS WA (US); Jian He, Los Angeles, CA WO 2008/030988 * 3/2008 (US); Chris Kaplan, Los Angeles, CA (US); Jee-Hyun Sim, Garden Grove, CA OTHER PUBLICATIONS (US) Adjic et al., “Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen”. Proc Natl Acad Sci USA. vol. 99, No. (73) Assignee: The Regents of the University of 22, Oct. 29, 2002, pp. 14434-14439. California, Oakland, CA (US) Brogden, "Antimicrobial peptides: pore formers or metabolic inhibi tors in 10 bacteria?”. Nature Reviews Microbiology, vol. 3, Mar. (*)c Notice:- r Subject to any site- the still Charles2005, pp. et 238-250. al., “In vivo antimicrobial activity of an essential oil patent 1s extended or adjusted under containing mouthrinse on interproximal plaque bacteria'. Journal of U.S.C. 154(b) by 167 days. Clinical Dentistry, vol. 11, 2000, pp. 94-97. Chen et al., “Inhibition 15 of growth of Streptococcus mutans, (21) Appl. No.: 12/701,443 methicillin-resistant Staphylococcus aureus, and Vancomycin-resis tant enterococci by kurarinone, a bioactive flavonoid isolated from (22) Filed: Feb. 5, 2010 Sophora flavescens”. Journal of Clinical Microbiology, vol.43, 2005, pp. 3574-3575. (65) Prior Publication Data Eckert et al., “Targeted killing of Streptococcus mutans by a phero mone-guided “smart' antimicrobial peptide'. Antimicrobial Agents US 2010/0316643 A1 Dec. 16, 2010 and Chemotherapy, vol. 50, No. 11, Oct. 23, 2006, pp. 3651-3657. Eckert et al., “Adding selectivity to antimicrobial peptides: rational Related U.S. Application Data design of a multidomain peptide against Pseudomonas spp. Anti microbial Agents and Chemotherapy, vol. 50, No. 4, 2006, pp. 1480 (60) Provisional application No. 61/224,825, filed on Jul. 1488. 10, 2009, provisional application No. 61/150,287, filed on Feb. 5, 2009. (Continued) (51) Int. Cl. Primary Examiner — Albert Navarro A 6LX39/395 (2006.01) Assistant Examiner — Ginny Portner (52) U.S. Cl...... 530/324; 424/134.1: 435/34: 514/21.3 (74) Attorney, Agent, or Firm — Gates & Cooper LLP (58) Field of Classification Search ...... None See application file for complete search history. (57) ABSTRACT This invention provides novel targeted antimicrobial compo (56) References Cited sitions. In various embodiments chimeric moieties are pro vided comprising an antimicrobial peptide attached to a pep U.S. PATENT DOCUMENTS tide targeting moiety that binds a bacterial Strain or species. 7,569,542 B2 * 8/2009 Eckert et al...... 514/1.1 7,846,895 B2 * 12/2010 Eckert et al...... 514, 2.6 37 Claims, 19 Drawing Sheets

TFFRFLNRGGG-k^M RKFLKKWL KKHRKHRKHRKHGGG MH(KH)-20 (mw 4884.91)

DAAN EAGGG-K/NM-FRKFLKKWILL KKHRKHRKHRKHGGG BL(KH)-20 (mw 4373.4)

TFFRFLNRGGG-K/NM-FRKFLKKWLL DAAN EAGGG

(mw 3798.01) US 8,389,679 B2 Page 2

OTHER PUBLICATIONS Patrzykat et al., “Sublethal concentrations of pleurocidin-derived antimicrobial peptides inhibit macromolecular synthesis in Eckert et al., “Enhancement of antimicrobial activity against 20 Escherichia coli'. Antimicrobial Agents and Chemotherapy, vol. 46, Pseudomonas aeruginosa by coadministration of G10KHc and No. 3, 2002, pp. 605-614. tobramycin'. Antimicrobial Agents and Chemotherapy, vol. 50, No. Qi et al., “Peptide pheromone induced cell death of Streptococcus mutans”. FEMS Microbiology Letters, vol. 251, 2005, pp. 321-326. 11, Aug. 28, 2006, pp. 3833-3838. Ruby et al., “Nature of symbiosis in oral disease'. Journal of Dental Fauchere et al., “Hydrophobic parameters-pi of amino-acid side Research, vol. 86, 2007, pp. 8-11. chains from the partitioning of N-acetyl-amino-acid amides'. Euro Strom et al., "Cloning and expression of the Pilin gene of pean Journal of Medicinal Chemistry, vol. 18, No. 4, 1983. pp. Pseudomonas aeruginosa PAK in Escherichia coli. Journal of Bac 369-375. teriology, vol. 165, No. 2, Feb. 1986, pp. 367-372. He et al., “Novel synthetic antimicrobial peptides against Streptococ ten Cate, "Biofilms, a new approach to the microbiology of dental cus mutans'. Antimicrobial Agents and Chemotherapy, vol. 51, No. plaque'. Odontology, vol. 94, 2006, pp. 1-9. Tincu et al., “Plicatamide, an antimicrobial octapeptide from Styela 4, Feb. 12, 2007, pp. 1351-1358. plicata hemocytes'. The Journal of Biological Chemistry, vol. 278, He et al., “Design and activity of a dual-targeted antimicrobial No. 15, Apr. 11, 2003, pp. 13546-13553. peptide'. Int J Antimicrob Agents, vol. 33, No. 6, Jun. 2009, pp. Zinder et al., “Genetic exchange in Salmonella'. Journal of Bacteri 532-537. ology, vol. 64, Apr. 18, 1952, pp. 679-699. Isturiz, “Global resistance trends and the potential impact on empiri Muhle et al., “Design of Gram-Negative Selective Antimicrobial cal therapy'. International Journal of Antimicrobial Agents, vol. 32. Peptides”. Biochemistry, vol. 40, 2001, pp. 5777-5785. No. S4, 2008, pp. S20 1-S206. International Preliminary Report on Patentability mailed Aug. 9. Lopez et al., “Global and regional burden of disease and risk factors, 2011 and Written Opinion of the International Search Authority 2001 : Systematic analysis of population health data'. The Lancet, mailed Dec. 27, 2010 for International Application No. PCT/ vol. 367, May 27, 2006, pp. 1747-1757. US2010/023376, pp. 1-5. Mokdad et al., “Actual causes of death in the United States'. JAMA, vol. 291, No. 10, Mar. 10, 2004, pp. 1238-1245. * cited by examiner U.S. Patent Mar. 5, 2013 Sheet 1 of 19 US 8,389,679 B2

Formula I

(91) R= -CH-CH (92) R = W (93) R = Et P = CHCHCOR, (94) R = -H R = H, alkyl, alkoxyl, alkenyl or alkynyl, (95) R = -COCH all from C to C, but preferably H (96) R = -CHO Me = methyl (97) OH R = -CH-CHOH (98) R = -CH=CHCOH (99), R = PR

FIG. 1

U.S. Patent Mar. 5, 2013 Sheet 3 of 19 US 8,389,679 B2

N NN N X

Compound M x Y 19 2 SC), 121 HOSiOSCH, CH, N(CH). H 123

125 Z CH, N, 2 126 Z: SON (CHOHOFi) 126 A. SOH

FIG. 3 U.S. Patent Mar. 5, 2013 Sheet 4 of 19 US 8,389,679 B2

2. N. . s 2. N. ? | - N. - N N N Cu H - ---

N

MonastIal Fast Blue E Monast Ial Fast Blue phthalocyanine) (CI PigittentBlue 15)

FIG. 4 U.S. Patent Mar. 5, 2013 Sheet 5 Of 19 US 8,389,679 B2

X R’ 2-1

S+ R Y R

R R R X Y

Methylene blue (CH)N N(CH) H N S Toluidine blue O (CH)N NH CH N S Neutral red (CH)N NH CH N NH Proflavine HN NH H CH NH Acridine Orange (CH),N N(CH) H CH NH Aminacrine H H H C-NH NH Ethacridine HN H OCH C-NH. NH

Merocyanine-type

NaOS Dicarbocyanine-type X R X S21a2N2nal I

X R X R Merocyanines Dicarbocyanines – O (MC540) S Et S Se H Se O (DHOCI)

FIG. 6 U.S. Patent Mar. 5, 2013 Sheet 6 of 19 US 8,389,679 B2

4' 5 4.

*KullW - X Y 2 1.

Psoraiens Angelicins

W X Y Z

O CH O O psoralen S CH O O thienocountarin C) N O O 8-azacoumarin O CH O S 2-thiofuranOCoumarin O CH () Se 2-Selenofuranocoumarin

FIG. 7

HO O OH

HO 21 Me

HO Me

HO O OH O H Hypericin Perylenequinonoids R R R R

R/R -CHC(OH)MeCH(COMe)- OMe Ove hypocrellin A RJR -CI ICMe=C(COMe)- OMe OMe hypocrellin B -CHCHMeCOPh -CHCHMeOCO-p-CHOH OMe OMe. Calphostin C

FIG. 8 U.S. Patent Mar. 5, 2013 Sheet 7 Of 19 US 8,389,679 B2

(~~~~)?%

FIG. 9 U.S. Patent Mar. 5, 2013 Sheet 8 of 19 US 8,389,679 B2

FIG. 10

s zzzzzzzzzz 8x. S$

\

s

FIG. 11

U.S. Patent Mar. 5, 2013 Sheet 10 of 19 US 8,389,679 B2

TFFRFLNRG GG-k^\f RKFLKKWLL KKHRKHRKHRKHGGG MH(KH)-20 (mw 4884.91) DAANEAGGG-k^M FIRKFLKKWLL KKHRKHRKHRKHGGG BL(KH)-20 (mw 4373.4)

TFFRFLNRGGG-k^MF RKFLKKWLL DAAN EAGGG M8(BL)-20 (mw 3798.01)

FIG. 13 U.S. Patent Mar. 5, 2013 Sheet 11 of 19 US 8,389,679 B2

8)

CO

mAU ..)

()

()

S.() ().() S() ().() Retention volume (mL)

FIG. 14A U.S. Patent Mar. 5, 2013 Sheet 12 of 19 US 8,389,679 B2

k &S&SS , is

.

38

Mass (m/z)

FIG. 14B U.S. Patent Mar. 5, 2013 Sheet 13 Of 19 US 8,389,679 B2

- BLOKH)-20 s -I-M8(KH-20 iron- s

0.9 --M8(BL)-20 S.

| -- BD2.20 s “No Peptide

Time (h) FIG. 15A

. -e-BLKH)-20

. --M80KH)-20

see B22

2 3. s 5 6 Time (h)

FIG. 15B U.S. Patent Mar. 5, 2013 Sheet 14 of 19 US 8,389,679 B2

-(- BLOKH)-20 --M8(KH-20 -A-M8(BL-20 M- B).() rNe Peptide

Time (i) FIG. 15C

-e- BL(KH-20 .6 -- M8(KH-20 -& s -

1.4 the AE8(BL)-2} - -e- BD2.20 a.

2 s S 6 Time (h

FIG. 15D U.S. Patent Mar. 5, 2013 Sheet 15 Of 19 US 8,389,679 B2

... " -(e-BL(KH)-20 ... " -- M8(KH-20 1.2 - Aro M8(BL-20 i. i -- B).2.2) 1 -i- No Peptide .9

2 S { Tinae (h)

FIG. 15E

St.

& Se

% % ; % 1E02 3 i. 2”. S8(Ki-2) AES(BL-2th BL KEI-20 B)2.20 intreated

FIG. 16 U.S. Patent Mar. 5, 2013 Sheet 16 of 19 US 8,389,679 B2

ZL‘61-I

U.S. Patent Mar. 5, 2013 Sheet 18 of 19 US 8,389,679 B2

:

se s s s cs S S S to r *t ri test83 & enties assaarea U.S. Patent Mar. 5, 2013 Sheet 19 Of 19 US 8,389,679 B2

FIG. 20 US 8,389,679 B2 1. 2 TARGETED ANTIMICROBAL MOIETIES more effector disclosed herein. Any targeting moiety dis closed herein can be attached to any one or more antimicro CROSS-REFERENCE TO RELATED bial peptide disclosed herein. APPLICATIONS In certain embodiments chimeric moieties are provided where the chimeric moieties comprise an effector attached to This application claims priority to U.S. Provisional Appli a peptide targeting moiety comprising or consisting of the cation No. 61/150,287, filed Feb. 5, 2009; and to U.S. Provi amino acid sequence of a peptide found in Table 2 and/or sional Application No. 61/224,825, filed Jul. 10, 2009, the Table 15. In certain embodiments the targeting peptide com disclosures of which are incorporated herein by reference in prises or consists of amino acid or retro or inverso or retro 10 inverso sequence or beta sequence of a peptide found in Table their entirety for all purposes. 2 and/or Table 15. In certain embodiments the effector com STATEMENT OF GOVERNMENTAL SUPPORT prises a moiety selected from the group consisting of a detect able label, an antimicrobial peptide, an antibiotic, and a pho Not Applicable tosensitizer. In certain embodiments the effector comprises 15 an antimicrobial peptide comprising the amino acid sequence FIELD OF THE INVENTION of a peptide found in Table 2, and/or Table 8, and/or Table 9, and/or Table 10. In certain embodiments the effector com prises an antibiotic found in Table 7. In certain embodiments The present invention relates to novel targeting peptides, the effector comprises a photosensitizer. In certain embodi novel antimicrobial peptides, chimeric moieties comprising ments the photosensitizer is selected from the group consist novel targeting and/or novel antimicrobial peptides and uses ing of a porphyrinic macrocycle, a porphyrin, a chlorine, a thereof. crown ether, an acridine, an azine, a phthalocyanine, a cya nine, a psoralen, and aperylenequinonoid. In certain embodi BACKGROUND OF THE INVENTION ments the photosensitizing agent is an agent shown in any of 25 FIGS 1-11. Antibiotic research at the industrial level was originally Also provided is a chimeric construct comprising a target focused on the identification of refined variants of already ing moiety attached to an antimicrobial peptide where the existing drugs. This resulted example, in the development of antimicrobial peptide comprises or consists of the amino acid antibiotics such as newer penicillins, cephalosporins, mac or retro or inverso or retro-inverso sequence of a peptide rolides, and fluoroquinolones. 30 found in Table 2. In certain embodiments the targeting moiety However, resistance to old and newer antibiotics among is a peptide that comprises or consists of the amino acid or bacterial pathogens is evolving rapidly, as exemplified by retro or inverso or retro-inverso or beta sequence of a peptide extended beta-lactamase (ESBL) and quinolone resistant found in Table 2, and/or Table 3, and/or Table 4, and/or Table gram-negatives, multi-resistant gonococci, methicillin resis 6, and/or Table 15. In certain embodiments, the targeting tant Staphylococcus aureus (MRSA), Vancomycin resistant 35 moiety comprises an antibody (e.g., an antibody identified in enterococci (VRE), penicillin non-susceptible pneumococci Table 5). In certain embodiments the targeting moiety is (PNSP) and macrollide resistant pneumococci and strepto chemically conjugated to the effector directly or via a linker. cocci (see, e.g., Panlilo et al. (1992) Infect. Control Hosp. In certain embodiments the targeting moiety is chemically Epidemiol., 13: 582-586: Morris et al. (1995) Ann Intern conjugated to the effector via a linker comprising a polyeth 40 ylene glycol (PEG). In certain embodiments the targeting Med., 123: 250-259, and the like). An overuse, or improper moiety is chemically conjugated to the effector via a non use, of antibiotics is believed to be of great importance for peptide linker found in Table 11. In certain embodiments the triggering and spread of drug resistant bacteria. Microbes where the targeting moiety is linked to the effector via a have, in many cases, adapted and are resistant to antibiotics peptide linkage. In certain embodiments the chimeric con due to constant exposure and improper use of the drugs. 45 struct is a fusion protein. In certain embodiments the linker is Drug resistant pathogens represent a major economic bur a peptide linker found in Table 11. In certain embodiments the den for health-care systems. For example, postoperative and chimeric moiety is functionalized with a polymer (e.g., poly other nosocomial infections will prolong the need for hospital ethylene glycol, a cellulose, a modified cellulose, etc.) to care and increase antibiotic drug expenses. It is estimated that increase serum halflife. the annual cost of treating drug resistant infections in the 50 Also provided are pharmaceutical compositions compris United States is approximately $5 billion. ing the chimeric construct(s)/chimeric moieties described herein in a pharmaceutically acceptable carrier. In certain SUMMARY OF THE INVENTION embodiments the composition is formulated as a unit dosage formulation. In certain embodiments the composition is for In certain embodiments, novel targeting moieties (e.g., 55 mulated for administration by a modality selected from the peptides) that specifically/preferentially bind to microorgan group consisting of intraperitoneal administration, topical isms (e.g., certain bacteria, yeasts, fungi, molds, viruses, administration, oral administration, inhalation administra algae, protozoa, and the like) are provided. The targeting tion, transdermal administration, Subdermal depot adminis moieties can be attached to effectors (e.g., detectable labels, tration, and rectal administration. drugs, antimicrobial peptides, etc.) to form chimeric con 60 Also provided is an antimicrobial composition comprising structs for specifically/preferentially delivering the effector to an isolated antimicrobial moiety comprising or consisting of and/or into the target organism. In certain embodiments novel the amino acid sequence of a peptide found in Table 2. In antimicrobial peptides that can be used to inhibit (e.g., kill certain embodiments the peptide comprises or consists of the and/or inhibit growth and/or proliferation) of certain micro amino acid or retro or inverso or retro-inverso sequence or organisms (e.g., certain bacteria, yeasts, fungi, molds, 65 beta sequence of a peptide found in Table 2. In certain viruses, algae, protozoa, and the like) are provided. Any tar embodiments the peptide is a peptide selected from the group geting moiety disclosed herein can be attached to any one or consisting of a peptide consisting of the amino acid sequence US 8,389,679 B2 3 4 of a peptide found in Table 2 comprising all L residues, a found in Table 2; and detecting the detectable label where the peptide consisting of the amino acid sequence of a peptide quantity and/or location of the detectable label is an indicator found in Table 2 comprising a peptide found in Table com of the presence of the microorganism and/or biofilm film. In prising all D residues, a peptide comprising the inverse of an certain embodiments the microorganism or biofilm is a bac amino acid sequence found in Table 2, a peptide comprising terium or a bacterial film. In certain embodiments the detect the retro-inverso form of a peptide found in Table 2, a peptide able label is a label selected from the group consisting of a found in Table 2 comprising a conservative Substitution, and radioactive label, a radio-opaque label, a fluorescent dye, a a peptide found in Table 2 comprising a substitution of a fluorescent protein, an enzymatic label, a colorimetric label, naturally occurring amino acid with a non-naturally occur and a quantum dot. ring amino acid. In certain embodiments the peptide com 10 prises no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative In certain embodiments compositions are also provided Substitutions. comprising a photosensitizing agent attached to a targeting Also provided is a composition comprising an isolated peptide where the targeting peptide comprising or consisting targeting moiety comprising or consisting of the amino acid of the amino acid or retro or inverso or retro-inverso sequence sequence of a peptide found in Table 2 or Table 15. In certain 15 of a peptide found in Table 2 or Table 15. In certain embodi embodiments the peptide comprises or consists of the amino ments the photosensitizing agent is an agent selected from the acid or retro or inverso or retro-inverso sequence or beta group consisting of a porphyrinic macrocycle, a porphyrin, a sequence of a peptide found in Table 2 or Table 15. In certain chlorine, a crown ether, an acridine, an azine, a phthalocya embodiments the peptide is a peptide selected from the group nine, a cyanine, a psoralen, and a perylenequinonoid. In cer consisting of a peptide consisting of the amino acid sequence tain embodiments the photosensitizing agent is an agent of a peptide found in Table 2 or Table 15 comprising all L shown in any of FIGS. 1-11. In certain embodiments the residues, a peptide consisting of the amino acid sequence of a photosensitizing agent is attached to the targeting peptide by peptide found in Table 2 comprising a peptide found in Table a non-peptide linker. In certain embodiments photosensitiz comprising all Dresidues, a peptide comprising the inverse of ing agent is attached to the targeting peptide by a linker an amino acid sequence found in Table 2 or Table 15, a 25 comprising a polyethylene glycol (PEG). In certain embodi peptide comprising the retro-inverso form of a peptide found ments the photosensitizing agent is attached to the targeting in Table 2 or Table 15, a peptide found in Table 2 or Table 15 peptide by a non-peptide linker found in Table 11. comprising a conservative Substitution, and a peptide found in In certain embodiments methods are provided for inhibit Table 2 or Table 15 comprising a substitution of a naturally ing the growth or proliferation of a microorganism and/or a occurring amino acid with a non-naturally occurring amino 30 acid. In certain embodiments the peptide comprises no more biofilm (e.g., a bacterium and/or a bacterial film), where the than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative substitutions. methods involve contacting the a microorganism and/or a In certain embodiments methods are provided for inhibit biofilm with a composition comprising a photosensitizing ing the growth and/or proliferation of a microorganism and/or agent attached to a targeting peptide as described herein. In a biofilm comprising a microorganism. The methods typi 35 certain embodiments the method further comprises exposing cally involve contacting the microorganism or biofilm with a the microorganism or biofilm to a light Source. In certain composition comprising an antimicrobial peptide comprising embodiments the microorganism is a microorganism selected or consisting of the amino acid sequence of a peptide found in from the group consisting of a bacterium, a yeast, a fungus, a Table 2 (e.g., the amino acid or retro or inverso or retro protozoan, and a virus. In certain embodiments the biofilm inverso sequence or beta sequence of a peptide found in Table 40 comprises a bacterial film. 2); and/or contacting the microorganism or biofilm with a In certain embodiments chimeric moieties are provided composition comprising an antimicrobial moiety attached to wherein the chimeric moiety comprises multiple targeting a targeting peptide comprising or consisting of the amino acid moieties attached to each other. In certain embodiments the sequence of a peptide found in Table 2 (e.g., the amino acid or targeting moieties are directly attached to each other. In cer retro or inverso or retro-inverso sequence or beta sequence of 45 tain embodiments the targeting moieties are attached to each a peptide found in Table 2). In certain embodiments the other via a peptide linker. In certain embodiments the target microorganism or biofilm is a bacterium or a bacterial film. In ing moieties are attached to each other via a non-peptide certain embodiments the targeting peptide is chemically con linker. In certain embodiments chimeric moieties are pro jugated to the antimicrobial peptide. In certain embodiments vided wherein the chimeric moiety comprises multiple effec the targeting peptide is linked directly to the antimicrobial 50 tors attached to each other. In certain embodiments the effec peptide. In certain embodiments the targeting peptide is linked to the antimicrobial peptide via a linker comprising a tors are directly attached to each other. In certain polyethylene glycol. In certain embodiments the targeting embodiments the effectors are attached to each other via a peptide is linked to the antimicrobial peptide via a non-pep peptide linker. In certain embodiments the effectors are tide linkage in Table 11. In certain embodiments the targeting 55 attached to each other via a non-peptide linker. peptide is linked to the antimicrobial peptide via a peptide In certain embodiments chimeric moieties are provided linkage. In certain embodiments the targeting peptide linked where the chimeric moiety comprises one or more targeting to the antimicrobial peptide is a fusion protein. In certain moieties attached to one or more effectors. In certain embodi embodiments the linker is a peptide linker in Table 11. ments the chimeric moiety comprises one or more of the In various embodiments methods are provided for detect 60 targeting moieties shown in Table 2, and/or Table 4 and/or ing a microorganism (e.g., bacteria, yeast, protozoan, Virus, Table 6, and/or Table 15 attached to a single effector. In algae, fungi, etc.) or biofilm comprising the microorganism. certain embodiments the chimeric moiety comprises one or The methods typically involve contacting the microorganism more effectors attached to a single targeting moiety. In certain or biofilm with a composition comprising a detectable label embodiments the chimeric moiety comprises one or more attached to a targeting peptide comprising the amino acid 65 effectors comprising one or more of the antimicrobial pep sequence of a peptide comprising or consisting of the amino tides shown in Table 2, and/or Table 8, and/or Table 9, and/or acid or retro or inverso or retro-inverso sequence of a peptide Table 10 attached to a single targeting moiety. In certain US 8,389,679 B2 5 6 embodiments the chimeric moiety comprises multiple target tive, if the N-substituted glycine derivative resembles the ing moieties attached to multiple effectors. original amino acid in hydrophilicity, hydrophobicity, polar ity, etc. Thus, for example, the following pairs of peptides DEFINITIONS would be considered “corresponding: 5 The term "peptide' as used herein refers to a polymer of amino acid residues typically ranging in length from 2 to (SEQ ID NO: 1) Ia. Asp-Arg-Val-Tyr-Ile-His-Pro-Phe about 50 residues. In certain embodiments the peptide ranges (Angiotensin II) in length from about 2, 3, 4, 5, 7, 9, 10, or 11 residues to about and 50, 45, 40, 45, 30, 25, 20, or 15 residues. In certain embodi 10 ments the peptide ranges in length from about 8, 9, 10, 11, or (SEQ ID NO: 2) 12 residues to about 15, 20 or 25 residues. Where an amino Ib. Asp-Arg-Val* -Tyr-Ile-His-Pro-Phe; acid sequence is provided herein, L-, D-, or beta amino acid (SEQ ID NO : 3) versions of the sequence are also contemplated as well as IIa. Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg retro, inversion, and retro-inversion isoforms. Peptides also 15 (Bradykinin) include amino acid polymers in which one or more amino and acid residues is an artificial chemical analogue of a corre (SEQ ID NO : 4) sponding naturally occurring amino acid, as well as to natu IIb : Arg-Pro-Pro-Gly-Phe-Ser* - Pro-Phe-Arg; rally occurring amino acid polymers. In addition, the term (SEO ID NO; 5) applies to amino acids joined by a peptide linkage or by other, IIIa : Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr “modified linkages” (e.g., where the peptide bond is replaced Pro-Leu-Val-Thr (B-Endorphin) ; by an O.-ester, a B-ester, a thioamide, phosphonamide, carbo and mate, hydroxylate, and the like (see, e.g., Spatola, (1983) (SEQ ID NO: 6) Chem. Biochem. Amino Acids and Proteins 7: 267-357), IIIb : Gly-Gly-Phe-Met-Ser* - Ser-Glu-Lys *-Ser-Gln where the amide is replaced with a saturated amine (see, e.g., 25 Serk-Pro-Leu-Val-Thr . Skiles et al., U.S. Pat. No. 4,496,542, which is incorporated herein by reference, and Kaltenbronn et al., (1990) Pp. 969 In these examples, “Val” refers to N-(prop-2-yl)glycine, 970 in Proc. 11th American Peptide Symposium, ESCOM “Phe' refers to N-benzylglycine, “Ser” refers to N-(2-hy Science Publishers, The Netherlands, and the like)). droxyethyl)glycine, “Leu refers to N-(2-methylprop-1-yl) The term “residue' as used herein refers to natural, syn 30 glycine, and "Ile refers to N-(1-methylprop-1-yl)glycine. thetic, or modified amino acids. Various amino acid ana The correspondence need not be exact: for example, N-(2- logues include, but are not limited to 2-aminoadipic acid, hydroxyethyl)glycine may substitute for Ser. Thr, Cys, and 3-aminoadipic acid, beta-alanine (beta-aminopropionic Met; N-(2-methylprop-1-yl)glycine may substitute for Val, acid), 2-aminobutyric acid, 4-aminobutyric acid, piperidinic Leu, and Ile. Note in IIIa and IIIb above that Ser is used to acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-ami 35 substitute for Thr and Ser, despite the structural differences: noisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic the sidechain in Ser is one methylene group longer than that acid, 2.4 diaminobutyric acid, desmosine, 2,2'-diami of Ser, and differs from Thr in the site of hydroxy-substitu nopimelic acid, 2,3-diaminopropionic acid, n-ethylglycine, tion. In general, one may use an N-hydroxyalkyl-substituted n-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3-hy glycine to Substitute for any polar amino acid, an N-benzyl- or droxyproline, 4-hydroxyproline, isodesmosine, allo-isoleu 40 N-aralkyl-substituted glycine to replace any aromatic amino cine, n-methylglycine, sarcosine, n-methylisoleucine, 6-n- acid (e.g., Phe, Trp, etc.), an N-alkyl-substituted glycine Such methyllysine, n-methylvaline, norvaline, norleucine, as N-butylglycine to replace any nonpolar amino acid (e.g., ornithine, and the like. These modified amino acids are illus Leu, Val, Ile, etc.), and an N-(aminoalkyl)glycine derivative trative and not intended to be limiting. to replace any basic polar amino acid (e.g., Lys and Arg). “B-peptides’ comprise of “Bamino acids”, which have 45 A “compound antimicrobial peptide' or “compound their amino group bonded to the B carbon rather than the AMP refers to a construct comprising two or more AMPs C-carbon as in the 20 standard biological amino acids. The joined together. The AMPs can be joined directly or through only commonly naturally occurring Bamino acid is 3-ala a linker. They can be chemically conjugated or, where joined 1C. directly together or through a peptide linker can comprise a Peptoids, or N-Substituted glycines, are a specific Subclass 50 fusion protein. of peptidomimetics. They are closely related to their natural In certain embodiments, conservative substitutions of the peptide counterparts, but differ chemically in that their side amino acids comprising any of the sequences described chains are appended to nitrogen atoms along the molecule's herein are contemplated. In various embodiments one, two, backbone, rather than to the C-carbons (as they are in natural three, four, or five different residues are substituted. The term amino acids). 55 “conservative substitution' is used to reflect amino acid sub The terms “conventional and “natural as applied to pep stitutions that do not substantially alter the activity (e.g., tides herein refer to peptides, constructed only from the natu antimicrobial activity and/or specificity) of the molecule. rally-occurring amino acids: Ala, Cys, Asp, Glu, Glu, Phe, Typically conservative amino acid Substitutions involve Sub Gly. His, Ile, Lys, Leu, Met, Asn. Pro, Gln, Arg, Ser. Thr, Val, stitution one amino acid for another amino acid with similar Trp, and Tyr. A compound of the invention “corresponds' to 60 chemical properties (e.g. charge or hydrophobicity). Certain a natural peptide if it elicits a biological activity (e.g., anti conservative substitutions include “analog substitutions' microbial activity) related to the biological activity and/or where a standard amino acid is replaced by a non-standard specificity of the naturally occurring peptide. The elicited (e.g., rare, synthetic, etc) amino acid differing minimally activity may be the same as, greater than or less than that of from the parental residue. Amino acid analogs are considered the natural peptide. In general. Such a peptoid will have an 65 to be derived synthetically from the standard amino acids essentially corresponding monomer sequence, where a natu without Sufficient change to the structure of the parent, are ral amino acid is replaced by an N-substituted glycine deriva isomers, or are metabolite precursors. Examples of Such US 8,389,679 B2 7 8 “analog substitutions” include, but are not limited to, 1) Lys The term “specificity' when used with respect to the anti Orn, 2) Leu-Norleucine, 3) Lys-LysTFA, 4) Phe-Phe(Gly, microbial activity of a peptide indicates that the peptide pref and 5) 6-amino butylglycine-S-amino hexylglycine, where erentially inhibits growth and/or proliferation and/or kills a Phegly refers to phenylglycine (a Phe derivative with a H particular microbial species as compared to other related rather than CH component in the R group), and LysTFA and/or unrelated microbes. In certain embodiments the pref refers to a Lys where a negatively charged ion (e.g., TFA) is erential inhibition or killing is at least 10% greater (e.g., LDso attached to the amine R group. Other conservative substitu is 10% lower), preferably at least 20%, 30%, 40%, or 50%, tions include “functional substitutions” where the general more preferably at least 2-fold, at least 5-fold, or at least chemistries of the two residues are similar, and can be suffi 10-fold greater for the target species. 10 “Treating or “treatment of a condition as used herein cient to mimic or partially recover the function of the native may refer to preventing the condition, slowing the onset or peptide. Strong functional Substitutions include, but are not rate of development of the condition, reducing the risk of limited to 1) Gly/Ala, 2) Arg/Lys, 3) Ser/Tyr/Thr, 4) Leu/Ile/ developing the condition, preventing or delaying the devel Val, 5) Asp/Glu, 6) Gln/ASn, and 7) Phe/Trp/Tyr, while other opment of symptoms associated with the condition, reducing functional substitutions include, but are not limited to 8) 15 or ending symptoms associated with the condition, generat Gly/Ala/Pro, 9) Tyr/His, 10) Arg/Lys/His, 11) Ser/Thr/Cys, ing a complete or partial regression of the condition, or some 12) Leu/Ile/Val/Met, and 13) Met/Lys (special case under combination thereof. hydrophobic conditions). Various “broad conservative sub The term “consisting essentially of when used with stations include Substitutions where amino acids replace respect to an antimicrobial peptide (AMP) or AMP motif as other amino acids from the same biochemical or biophysical described herein, indicates that the peptide or peptides grouping. This is similarity at a basic level and stems from encompassed by the library or variants, analogues, or deriva efforts to classify the original 20 natural amino acids. Such tives thereof possess Substantially the same or greater antimi substitutions include 1) nonpolar side chains: Gly/Ala? Val/ crobial activity and/or specificity as the referenced peptide. In Leu/Ile/Met/Pro/Phe/Trp, and/or 2) uncharged polar side certain embodiments Substantially the same or greater anti chains Ser/Thr/ASn/Gln/Tyr/Cys. In certain embodiments 25 microbial activity indicates at least 80%, preferably at least broad-level Substitutions can also occur as paired substitu 90%, and more preferably at least 95% of the anti microbial tions. For example, any hydrophilic neutral pair Ser, Thr, activity of the referenced peptide(s) against a particular bac Gln, Asn., Tyr, Cys--Ser. Thr, Gln, Asn., Tyr, Cys can may be terial species (e.g., S. mutans). replaced by a charge-neutral charged pair Arg, Lys, His+ The term “porphyrinic macrocycle” refers to a porphyrin or Asp, Glu. The following six groups each contain amino 30 porphyrin derivative. Such derivatives include porphyrins acids that are typical conservative Substitutions for one with extra rings ortho-fused, or orthoperifused, to the porphy another: 1) Alanine (A), Serine (S). Threonine (T); 2) Aspar rin nucleus, porphyrins having a replacement of one or more tic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine carbon atoms of the porphyrin ring by an atom of another (Q); 4) Arginine (R), Lysine (K), Histidine (H); 5) Isoleucine element (skeletal replacement), derivatives having a replace (I), Leucine (L), Methionine (M), Valine (V); and 6) Pheny 35 ment of a nitrogen atom of the porphyrin ring by an atom of lalanine (F), Tyrosine (Y), Tryptophan (W). another element (skeletal replacement of nitrogen), deriva In certain embodiments, targeting peptides, antimicrobial tives having Substituents other than hydrogen located at the peptides, and/or STAMPs compromising at least 80%, pref peripheral (meso-, ..beta.-) or core atoms of the porphyrin, erably at least 85% or 90%, and more preferably at least 95% derivatives with saturation of one or more bonds of the por or 98% sequence identity with any of the sequences described 40 phyrin (hydroporphyrins, e.g., chlorins, bacteriochlorins, iso herein are also contemplated. The terms “identical' or per bacteriochlorins, decahydroporphyrins, corphins, pyrrocor cent “identity,” refer to two or more sequences that are the phins, etc.), derivatives obtained by coordination of one or same or have a specified percentage of amino acid residues more metals to one or more porphyrinatoms (metalloporphy that are the same, when compared and aligned for maximum rins), derivatives having one or more atoms, including pyr correspondence, as measured using one of the following 45 rolic and pyrromethenyl units, inserted in the porphyrin ring sequence comparison algorithms or by visual inspection. (expanded porphyrins), derivatives having one or more With respect to the peptides of this invention sequence iden groups removed from the porphyrin ring (contracted porphy tity is determined over the full length of the peptide. For rins, e.g., corrin, corrole) and combinations of the foregoing sequence comparison, typically one sequence acts as a refer derivatives (e.g. phthalocyanines, porphyrazines, naphthalo ence sequence, to which test sequences are compared. When 50 cyanines, Subphthalocyanines, and porphyrin isomers). Cer using a sequence comparison algorithm, test and reference tain porphyrinic macrocycles comprise at least one 5-mem sequences are input into a computer, Subsequence coordi bered ring. nates are designated, if necessary, and sequence algorithm As used herein, an “antibody refers to a protein consisting program parameters are designated. The sequence compari of one or more polypeptides Substantially encoded by immu son algorithm then calculates the percent sequence identity 55 noglobulin genes or fragments of immunoglobulin genes. for the test sequence(s) relative to the reference sequence, The recognized immunoglobulin genes include the kappa, based on the designated program parameters. Optimal align lambda, alpha, gamma, delta, epsilon and mu constant region ment of sequences for comparison can be conducted, e.g., by genes, as well as myriad immunoglobulin variable region the local homology algorithm of Smith & Waterman (1981) genes. Light chains are classified as either kappa or lambda. Adv. Appl. Math. 2: 482, by the homology alignment algo 60 Heavy chains are classified as gamma, mu, alpha, delta, or rithm of Needleman & Wunsch (1970).J. Mol. Biol. 48: 443, epsilon, which in turn define the immunoglobulin classes, by the search for similarity method of Pearson & Lipman IgG, IgM, IgA, Ig|D and IgE, respectively. (1988) Proc. Natl. Acad. Sci., USA, 85: 2444, by computer A typical immunoglobulin (antibody) structural unit is ized implementations of these algorithms (GAP, BESTFIT, known to comprise a tetramer. Each tetramer is composed of FASTA, and TFASTA in the Wisconsin Genetics Software 65 two identical pairs of polypeptide chains, each pair having Package, Genetics Computer Group, 575 Science Dr. Madi one “light” (about 25kD)andone “heavy chain (about 50-70 son, Wis.), or by visual inspection. kD). The N-terminus of each chain defines a variable region US 8,389,679 B2 9 10 of about 100 to 110 or more amino acids primarily respon TABLE 1 - continued sible for antigen recognition. The terms variable light chain (V) and variable heavy chain (V) refer to these light and Amino acid abbreviations. heavy chains respectively. Abbreviation Antibodies exist as intact immunoglobulins or as a number 5 of well characterized fragments produced by digestion with Name 3 Letter 1. Luetter various peptidases. Thus, for example, pepsin digests an anti Glutamine Glin Q body below the disulfide linkages in the hinge region to produce F(ab)', a dimer of Fab which itself is a light chain Glycine Gly G joined to V-C1 by a disulfide bond. The F(ab), may be 10 reduced under mild conditions to break the disulfide linkage Histidine His H in the hinge region thereby converting the (Fab') dimer into Homo serine Hse an Fab' monomer. The Fab' monomer is essentially an Fab with part of the hinge region (see, Fundamental Immunology, Isoleucine Ile I W. E. Paul, ed., Raven Press, N.Y. (1993), for a more detailed 15 description of other antibody fragments). While various anti Leucine Luell L body fragments are defined in terms of the digestion of an Lysine Lys K intact antibody, one of skill will appreciate that such Fab' fragments may be synthesized de novo either chemically or Methionine Met M by utilizing recombinant DNA methodology. Thus, the term Methionine sulfoxide Met (O) antibody, as used herein also includes antibody fragments either produced by the modification of whole antibodies or Methionine methylsulfonium Met (S-Me) - synthesized denovo using recombinant DNA methodologies, Norleucine Nile including, but are not limited to, Fab', IgG, IgM, IgA, scEv. dAb, nanobodies, unibodies, and diabodies. 25 Phenylalanine Phe In certain embodiments antibodies and fragments of the present invention can be bispecific. Bispecific antibodies or Proline Pro P fragments can be of several configurations. For example, Serine Ser S bispecific antibodies may resemble single antibodies (or anti body fragments) but have two different antigen binding sites 30 Threonine Thir T (variable regions). In various embodiments bispecific anti Tryptophan Trp W bodies can be produced by chemical techniques (Kranz et al. (1981) Proc. Natl. Acad. Sci., USA, 78: 5807), by “polydoma' Tyrosine Tyr Y techniques (see, e.g., U.S. Pat. No. 4,474,893), or by recom binant DNA techniques. In certain embodiments bispecific 35 Waline Wall W antibodies of the present invention can have binding speci episilon-aminocaproic acid Ahx J ficities for at least two different epitopes, at least one of which (NH’-(CH2) s-COOH) is an epitope of a microbial organism. The microbial binding 4-aminobutanoic acid gAbu antibodies and fragments can also be heteroantibodies. Het (NH. (CH) -COOH) eroantibodies are two or more antibodies, orantibody binding 40 fragments (e.g., Fab) linked together, each antibody or frag tetrahydro isoquinoline-3- O ment having a different specificity. carboxylic acid The term “STAMP refers to Specifically Targeted Anti Lys (N (epsilon) - trifluoroacetyl) KITFA) Microbial Peptides. An MH-STAMP is a STAMP bearing two or more targeting domains (i.e., a multi-headed STAMP). 45 C.-aminoisobutyric acid Aib B In various embodiments the amino acid abbreviations shown in Table 1 are used herein. BRIEF DESCRIPTION OF THE DRAWINGS TABLE 1. 50 FIG. 1 shows some illustrative porphyrins (compounds Amino acid abbreviations. 92-99) suitable for use as targeting moieties and/or antimi crobial effectors. Abbreviation FIG. 2 shows some illustrative porphyrins (compounds Name 3 Letter 1. Luetter 100-118) suitable for use as targeting moieties and/orantimi 55 crobial effectors. Alanine Ala A. FIG. 3 shows some illustrative porphyrins (in particular BAlanine (NH-CH-CH-COOH) Ala phthalocyanines) (compounds 119-128) suitable for use as targeting moieties and/or antimicrobial effectors. Arginine Arg R FIG. 4 illustrates the structures of two phthalocyanines, 60 Monoastral Fast Blue Band Monoastral Fast Blue G suitable Asparagine Asn N for use as targeting moieties and/or antimicrobial effectors. Aspartic Acid Asp D FIG.5 illustrates certain azine photosensitizers suitable for use as targeting moieties and/or antimicrobial effectors in the Cysteine Cys C compositions and methods described herein. Glutamic Acid Glu E 65 FIG. 6 shows illustrative cyanine suitable for use as target ing moieties and/or antimicrobial effectors in the composi tions and methods described herein. US 8,389,679 B2 11 12 FIG. 7 shows illustrative psoralen (angelicin) photosensi epidermidis (Se) planktonic cells were mixed with tizers suitable for use as targeting moieties and/or antimicro MH-STAMPs (as indicated in the figure) and treated 24 h. bial effectors in the compositions and methods described After incubation, cfu/mL of remaining constituent species herein. were quantitated after plating to selective media. * indicates FIG. 8 shows illustrative hypericin and the perylene under 200 surviving cfu/mL recovered. quinonoid pigments suitable for use as targeting moieties FIG. 17 depicts the results of minimal inhibitory concen and/or antimicrobial effectors in the compositions and meth tration (MIC) assays, conducted against S. mutans and a panel ods described herein. of bacteria, including two oral streptococci, S. sanguinis and FIG. 9 shows illustrative acridines suitable for use as tar S. sobrinus, to gauge Library 1 STAMP (SEQID NOS:1969 geting moieties and/or antimicrobial effectors in the compo 10 1976) antimicrobial activity and S. mutans-selectivity. sitions and methods described herein. FIG. 18 shows the results of MIC assays of STAMPs com FIG. 10 illustrates the structure of the acridine Rose Ben prising targeting peptide 2 1 conjugated to one of five gal. AMPs: RWRWRWF (2c-4; SEQ ID NO:1860), FKKFWK FIG. 11 illustrates various crown ethers suitable for use as WFRRF (B-33; SEQID NO:1821), IKQLLHFFQRF (B-38; targeting moieties and/or antimicrobial effectors in the com 15 SEQID NO:1826), RWRRLLKKLHHLLH (c.-11: SEQ ID positions and methods described herein. NO:1877), and LQLLKQLLKLLKQF (C-7: SEQ ID FIG. 12 schematically shows some illustrative configura NO:1873. Each targeting peptide is attached at the C- or tions for chimeric constructs described herein. A: Shows a N-terminus to an AMP utilizing a linker selected from: L1, single targeting moiety T1 attached to a single effector E1 by SGG (L6: SEQID NO:1938), L3, and LC. The linkers in FIG. a linker/spacer L. B: Shows multiple targeting moieties T1, 18 are designated by their abbreviation and shown in paren T2, T3 attached directly to each other and attached by a linker thesis in the STAMP name (e.g. "21 (L1),C-4”). MIC assays L to a single effector E1. In various embodiments T1, T2, and were conducted against a panel of bacteria, including S. T3, can be domains in a fusion protein. C: Shows multiple mutans (S. mu), S. gordonii (S. gor), S. sanguinis (S. san), and targeting moieties T1, T2, T3 attached to each other by linkers S. mitis (S. mit), to gauge differences in activity between L and attached by a linker L to a single effector E1. In various 25 attaching the targeting peptide to the C- or N-terminus of the embodiments T1, T2, and T3, can be domains in a fusion AMP region or differences in activity between the linker protein. D: Shows a single targeting moiety T1 attached by a used. linker L to multiple effectors E1, E2, and E3 joined directly to FIG. 19 shows the killing kinetics of selected peptides each other. E.: Shows a single targeting moiety T1 attached by against oral Streptococci. All tested bacteria, (A) S. mitis a linker L to multiple effectors E1, E2, and E3 joined to each 30 (Smit), (B) S. gordonii (Sgor), (C) .S. sanguinis (Ssan), and other by linkers L. F. Shows multiple targeting moieties (D) S. mutans (Smut), were treated with peptide solutions at joined directly to each other and by a linker L to multiple 25 g/mL for 30s to 2 hand survivors plated. Data represent effectors joined to each other by linkers L. G: Shows multiple an average of three independent experiments. targeting moieties joined to each other by linkers L and by a FIG. 20 illustrates the inhibitory activity of STAMPs linker L to multiple effectors joined to each other by linkers L. 35 against S. mutans biofilms. S mutans monoculture biofilms In various embodiments T1, T2, and T3, and/or E1, E2, and were grown and exposed to a 25 g/mL of STAMP. unmodi E3 can be domains in a fusion protein. H: Illustrates a fied parental AMP or oral antiseptic (for 1 min), washed, and branched configuration where multiple targeting moieties are replenished with fresh medium. Biofilm recovery was moni linked to a single effector. I: Illustrates a dual branched con tored after 4 h by A600. Data represent an average of three figuration where multiple targeting moieties are linked to 40 experiments. multiple effectors. J: Illustrates a branched configuration where multiple targeting moieties are linked to multiple DETAILED DESCRIPTION effectors where the effectors are joined to each other in a linear configuration. In various embodiments this invention is based on the FIG. 13 illustrates various MH-STAMPs used in Example 45 development of a method for the rapid identification and 1. The design, sequence, and observed mass (m/z) for synthesis of Small peptides from sequenced genomes for the M8(KH)-20, BL(KH)-20, and M8(BL)-20. purposes of quickly screening these molecules for diverse FIGS. 14A and 14B show HPLC and MS spectra of biological activities. Previously, small secreted peptides had M8(KH)-20. The quality of the completed MH-STAMP was to be identified by direct collection (purification of spent analyzed by HPLC (FIG. 14A) and MALDI mass spectros 50 microbial growth medium or biological tissue/fluid), or by copy (FIG. 14B). At UV absorbance 215 nm (260 and 280 nm identification through differential microarray analysis or as a are also plotted), a single major product was detected by by-product of genetic operon characterization. Both are HPLC (* retention volume 11.04 mL). After fraction collec multi-step processes that terminate at peptide identification; tion, the correct mass (m/z) for single-charged M8(KH)-20, several separate enterprises are required to synthesize or 4884.91 (marked by *), was observed for this peak. Y-axis: 55 sequence any peptides for characterization. Additionally, 14A, maU miliabsorbance units; 14B, percent intensity. because of their Small size and lack of protein domain FIG. 15A-15E show growth inhibitory activity of MH homologies, Small peptides are frequently overlooked when STAMPs. Monocultures of S. mutans (FIG. 15A); P aerugi describing biological systems, though many organisms con nosa (FIG. 15B); S. epidermidis (FIG. 15C): S. aureus (FIG. tain numerous peptide-sized open reading frames (ORFs). 15D); or E. coli (FIG. 15E); were treated with peptides (as 60 Genomic sequence analysis tools already in the public indicated in the figure) for 10 min. Agent was then removed domain and high-throughput Solid phase peptide chemistry and fresh media returned. Culture recovery was measured were used to rapidly identify and synthesize biologically over time (OD600). Plots represent the average of at least 3 active peptides. Using sequences and sometimes annotated independent experiments with standard deviations. genomes, genomes were scanned, by hand or with a search FIG. 16 illustrates the selective activity of dual-targeted 65 algorithm, for ORFs predicted to encode peptides of less than and single-targeted MH-STAMPs in mixed culture. A mix for example, 50-60 amino acids (ignoring small tRNA ORFs ture of Paeruginosa (Pa), S. mutans (Sm), E. coli (Ec), and S. or other well characterized genes). US 8,389,679 B2 13 14 Once noted, these peptides were batch synthesized on a residues, and beta peptide sequences. It will also be appreci multiplex peptide synthesizer, yielding 5-10 mg of each pep ated in addition to the D-form and L-form and beta-peptide tide that could readily be screened for biological activity (e.g., sequences this invention also contemplates retro and retro binding activity and/or antimicrobial activity. inverso forms of each of these peptides. In retro forms, the Accordingly, in certain embodiments, this invention per direction of the sequence is reversed. In inverse forms, the tains to the identification of novel peptides (see, e.g., Table 2) chirality of the constituent amino acids is reversed (i.e., L that specifically or preferentially bind particular microorgan form amino acids become D form amino acids and D form isms (e.g., bacteria) and/or that have antimicrobial activity. In amino acids become L formamino acids). In the retro-inverso certain embodiments these peptides can be attached to effec form, both the order and the chirality of the amino acids is tors (e.g., drugs, labels, etc.) and used as targeting moieties 10 reversed. Thus, for example, a retro form of the of the peptide thereby providing a chimeric moiety that preferentially or Smu11 (MKNLIETVEKFLTYSDEKLEELAKKN specifically delivers the effector to a target microorganism, a QALREEISROKSK, SEQ ID NO:11) has the sequence population of target microorganisms, a microbial film com KSKQRSIEERLAQNKKALEELKED prising the target microorganism(s), a biofilm comprising the SYTLFKEVTEILNKM (SEQID NO:10). Where the Smul1 target microorganism(s), and the like. 15 peptide comprises all L amino acids, the inverse form will In certain embodiments these peptides can be exploited for comprise all D amino acids and the retro-inverso (retro-in their antimicrobial activity to inhibit the growth or prolifera verse) form will have the sequence of SEQ ID NO:10 and tion of a microorganism and/or to inhibit the formation and/or comprise all D form amino acids. Also contemplated are growth of a biofilm comprising the microorganism. These peptides having the amino acid sequences or retroamino acid antimicrobial peptides can be used alone, in conjunction with sequences of the peptides in Table 2 (or the other tables shown other agents (e.g., antibacterial agents), and/or they can be herein) and comprising one, two, three, four, five, six, seven, coupled to a targeting moiety to provide a chimeric moiety eight, nine, or ten conservative Substitutions, but retaining that preferentially directs the antimicrobial peptide to a target Substantially the same binding and/or antimicrobial activity. tissue and/or to a target organism (e.g., a bacterium, a popu Also contemplated are peptides having the amino acid lation of target microorganisms, a microbial film, a biofilm, 25 sequences or retro amino acid sequences of the peptides in and the like). Table 2 (or other tables herein) and comprising one, two, In certain embodiments the antimicrobial peptides and/or three, four, five, six, seven, eight, nine, or ten deletions, but the chimeric moieties described herein can be formulated retaining Substantially the same binding and/or antimicrobial with a pharmaceutically acceptable carrier to form a pharma activity. cological composition. 30 In various embodiments, chimeric moieties comprising The amino acid sequences of illustrative peptides of this one or more of the targeting peptides found in Table 2 invention having antimicrobial and/or targeting activity attached to one or more effectors (e.g., antimicrobial peptides against methicillin resistant Streptococcus mutans, Strepto as described herein) are contemplated. In various embodi coccus pyogenes, and/or Treponema denticola is shown in ments, one or more of the antimicrobial peptides found in Table 2. As with the other peptides described herein, it will be 35 Table 2 used as effectors or attached to one or more targeting recognized that these peptides can comprise all "L' form moieties (e.g., targeting peptides, targeting antibodies, and residues, all “D' form residues, mixtures of “L’ and “D’ the like) to form chimeric moieties are contemplated. TABL E 2 Peptides having antimicrobia and/or targeting activity against one or more of the foll owing: Streptococcus mutans, streptococcus pyogenes, and Treponema denticola.

SEQ ID Amino Acid Sequence ID NO

Smu11 MKNLIETWEKFLTYSDEKLEELAKKNOALREEISROKSK 1.

Smul. 18 GGRAGRIKKLSOKEAEPFEN 2

Smula 1 MFIRSKLRRWDFSGWRRGNKHFLLDKLLITLWK 3

Smul68 MSALFYDTLAAIWISIAGWDARWGH 4.

Smul150 GGKWSGGEAWAAIGICATASAAIGGLAGATLWTPYCWGTWGLI 5 RSH

Smul151 DKQAADTFLSAWGGAASGFTYCASNGWWHPYILAGCAGVGA 6 WGSWWFPH

Smu223 c GGKYLFLASKTKEYFKSHFREIMIDW 7

Smu225c MFISFWDCIONIEKIEKELLKIGITDIOINODAGWLY 8

Smu277 YLTEIEGEGLGLGICLGLVGFAGGFAHGVWOGAGVGTAIEPGY 9 GTIIGALVDGWGODLIYGGAGFAAGYSL

Smu283 GGFDWKGWAASYLAMGTAALGGLACTTPWGAWLYLGAEWCA 2O GAAWIYYGAN

Smu299 c GGGLYDGANGYAYRDSOGHWAYKVTKTPAOALTDVVVNSW 21 ASGAASFAAYA

US 8,389,679 B2 17 18 TABLE 2 - continued Peptides having antimicrobial and/or targeting activity against one or more of the following: Streptococcus mutans, streptococcus pyogenes, and Treponema denticola.

SEQ ID Amino Acid Sequence ID NO

Smull 896c GGFGWDSIWRGFKCWAGTAGTIGTGALGGSATGGLTLPIIGHW 52 SGGIIGGISGAGWGIASFC

Smul899 MLSISORTDRVIVMDKGKIIEEGTHSELIAANGFYHHLFNK 53

Smulle O2c GGAFYORKENVISLDPREWLGFNVTEK 54

Smu1903c GGNIFEYFLE 55

Smu19 Osc GGGRAPRCAALWGASIYDGLAWWGDPWGWAMAAGTIAAGSFC 56

Smull 906c GGCSWKGADKAGFSGGWGGLIGAGGNPWGGWLGIAGGLDAY f GELWGGN

Smulle O7 MEONILNGSYFWLNGKNAKFLLEIDKLTLPDKLATLPWPHOVR 58

Smule 14c GGGRGWNCAAGIALGAGOGYMATAGGTAFLGPYAIGTGAFG 59 AIAGGIGGALNSCG

Smule 15 GGSGSLSTFFRLFNRSFTOALGK 6 O

Smull 948 GGVFSVLKHTTWPTRKOSWHDFISILEYSAFFALVIFIFDKLLTL 61 GLAELLKRF

Smu1.968c GGSWLGKHALFILLKAGFKAYELAGAFEGWKGMHLPTEKC 62

Smule 72c GGLVMNDETIYLFTYENGOISYEEDKRDCSKNV 63

Smu2105 MRFLKDELSVSWRLOEKSIEALPFRTKIEIEIESDNOIKTL 64

Smu2106c GGASGEKILEKLIHERKCOLTONROIWLKTDLNNLMKDFYK 65

Smu2121c GGIILAKAADLAEIERIISEDPFKINEIANYDIIEFCPTKSSKAFEK 66

Uses of Targeting Moieties. ing by a Subsequently administered second targeting species. When exploited for their targeting activity, the novel tar 40 Once Sufficient accretion of the primary targeting species (the geting peptides described herein (see, e.g., Table 2) can be chimeric molecule) is achieved, a second targeting species used to preferentially or specifically deliver an effector to a comprising (i) a diagnostic or therapeutic agent and (ii) a second targeting moiety, that recognizes the available binding microorganism (e.g., a bacterium, a fungus, a protozoan, a site of the primary targeting species, is administered. yeast, an algae, etc.), to a bacterial film comprising the micro An illustrative example of a pre-targeting protocol is the organism, to a biofilm comprising the microorganism, and the 45 biotin-avidin System for administering a cytotoxic radionu like. Where the effector comprises an epitope tag and/or a clide to a tumor. In a typical procedure, a monoclonal anti detectable label, binding of the targeting moiety provides an body targeted against a tumor-associated antigen is conju indication of the presence and/or location, and/or quantity of gated to avidin and administered to a patient who has a tumor the target (e.g., target microorganism). Thus targeting moi recognized by the antibody. Then the therapeutic agent, e.g., eties are thus readily adapted for use in in vivo diagnostics, 50 a chelated radionuclide covalently bound to biotin, is admin and/or ex vivo assays. Moreover, because of Small size and istered. The radionuclide, via its attached biotin is taken up by good stability, the microorganism binding peptides are well the antibody-avidin conjugate pretargeted at the tumor. Examples of pre-targeting biotin/avidin protocols are Suited for microassay systems (e.g., microfluidic assays (Lab described, for example, in Goodwin et al., U.S. Pat. No. on a Chip), microarray assays, and the like). 4,863,713; Goodwin et al. (1988) J. Nucl. Med. 29: 226: In certain embodiments the microorganism binding pep 55 Hnatowich et al. (1987).J. Nucl. Med. 28: 1294: Oehr et al. tides (targeting peptides) can be attached to an effector that (1988).J. Nucl. Med. 29: 728; Klibanov et al. (1988).J. Nucl. has antimicrobial activity (e.g., an antimicrobial peptide, an Med. 29: 1951: Sinitsyn et al. (1989).J. Nucl. Med. 30: 66: antibacterial and/or antifungal, a vehicle that contains an Kalofonos et al. (1990).J. Nucl. Med. 31: 1791; Schechter et antibacterial orantifungal, etc. In various embodiments these al. (1991) Int. J. Cancer 48:167; Paganelli et al. (1991) Can chimeric moieties can be used in vivo, or ex vivo to prefer 60 cer Res. 51: 5960; Paganelli et al. (1991) Nucl. Med. Com entially inhibit or kill the target organism(s). mun. 12: 211; Stickney et al. (1991) Cancer Res. 51: 6650: In certain embodiments the targeting peptides can be used and Yuan et al. (1991) Cancer Res. 51:3119. in various pre-targeting protocols. In pre-targeting protocols, It will be recognized that the tumor-specific antibody used a chimeric molecule is utilized comprising a primary target for cancer treatments can be replaced with a microorganism ing species (e.g. a microorganism-binding peptide) that spe 65 binding peptide of the present invention and similar pre cifically binds the desired target (e.g. a bacterium) and an targeting strategies can be used to direct labels, antibiotics, effector that provides a binding site that is available for bind and the like to the target organism(s). US 8,389,679 B2 19 20 Three-step pre-targeting protocols in which a clearing utilized as extracellular scaffold, adhesin or binding site, agent is administered after the first targeting composition has induction or Suppression of host immune response, induction localized at the target site also have been described. The or Suppression of bacterial/fungal antimicrobial molecule clearing agent binds and removes circulating primary conju production, quorum-sensing, induction of Swarming behav gate which is not bound at the target site, and prevents circu ior, apoptosis or necrosis inducing in eukaryotic cells, affect lating primary targeting species (antibody-avidin or conju ing control of or inducing the initiation of cell cycle in eukary gate, for example) from interfering with the targeting of otes, in archaea or prokaryotes, induces autolysis or active agent species (biotin-active agent conjugate) at the programmed cell death, inhibition of phage?virus attachment target site by competing for the binding sites on the active or replication, evasion of innate immunity, induction or inhi agent-conjugate. When antibody-avidin is used as the pri 10 bition of genetic transformation or transduction competence, mary targeting moiety, excess circulating conjugate can be induction or inhibition of pilus-mediated conjugation, induc cleared by injecting a biotinylated polymer Such as biotiny tion or inhibition of mating behavior in bacteria and fungi, lated human serum albumin. This type of agent forms a high induction or inhibition of nodule formation or metabolic molecular weight species with the circulating avidin-anti compartmentalization, metal, ion, or nutrient binding, acqui body conjugate which is quickly recognized by the hepato 15 sition or inhibition of metal, ion, or nutrient binding and biliary system and deposited primarily in the liver. acquisition, and the like. Examples of these protocols are disclosed, e.g., in PCT These applications of the peptides described herein are Application No. WO93/25240; Paganelli et al. (1991) Nucl. intended to be illustrative and not limiting. Using the teaching Med. Comm., 12: 211-234: Oehr et al. (1988).J. Nucl. Med., provided herein, other uses will be recognized by one of skill 29: 728-729; Kalofonos et al. (1990).J. Nucl. Med., 31: 1791 in the art. 1796; Goodwin et al. (1988).J. Nucl. Med., 29: 226-234; and Design and Construction of Chimeric Moieties. the like). In various embodiments this invention provides chimeric These applications of microorganism binding peptides of moieties comprising one or more targeting moieties attached this invention are intended to be illustrative and not limiting. to one or more effectors. The targeting moieties are typically Using the teaching provided herein, other uses will be recog 25 selected to preferentially bind to a target microorganism (e.g., nized by one of skill in the art. bacteria, virus, fungi, yeast, alga, protozoan, etc.), or group of Uses of Antimicrobial Peptides. microorganisms (e.g., gram-negative or gram-positive bacte When exploited for their antimicrobial activity, the novel ria, particular genus, particular species, etc.) In certain antimicrobial peptides described herein (see, e.g., Table 2) embodiments the targeting moiety comprises one or more of can be used to inhibit the growth and/or proliferation of a 30 the targeting peptides shown in Table 2, and/or Table 4 and/or microbial species and/or the growth or proliferation of a Table 6. In certain embodiments the targeting moiety com biofilm comprising the microbial species. In various embodi prises non-peptide moieties (e.g., antibodies, receptor, recep ments the peptides can be formulated individually, in combi tor ligand, lectin, and the like). nation with each other, in combination with other antimicro The effector typically comprises one or more moieties bial peptides, and/or in combination with various 35 whose activity is to be delivered to the target antibacterial agents to provide antimicrobial reagents and/or microorganism(s), and/or to a biofilm comprising the target pharmaceuticals. microorganism(s), and/or to a cell or tissue comprising the In various embodiments, the antimicrobial peptides target microorganism(s), and the like. In certain embodiments described herein can be formulated individually, in combina the targeting moiety comprises one or more antimicrobial tion with each other, in combination with other antimicrobial 40 peptide(s) as described herein (see, e.g., antimicrobial pep peptides, and/or in combination with various antibiotic (e.g., tides in Table 2, and/or Table 8, and/or Table 9, and/or Table antibacterial) agents in “home healthcare' formulations. 10), an antibiotic (including, but not limited to a steroid Such formulations include, but are not limited to toothpaste, antibiotic) (see, e.g., Table 7), a detectable label, a porphyrin, mouthwash, tooth whitening strips or Solutions, contact lens a photosensitizing agent, an epitope tag, a lipid or liposome, storage, wetting, or cleaning solutions, dental floss, tooth 45 a nanoparticle, a dendrimer, and the like. picks, toothbrush bristles, oral sprays, oral lozenges, nasal In certain embodiments one or more targeting moieties are sprays, aerosolizers for oral and/or nasal application, wound attached to a single effector (see, e.g. FIG. 12). In certain dressings (e.g., bandages), and the like. embodiments one or more effectors are attached to a single In various embodiments the antimicrobial peptides targeting moiety. In certain embodiments multiple targeting described herein can be formulated individually, in combina 50 moieties are attached to multiple effectors. The targeting moi tion with each other, in combination with other antimicrobial ety(s) can be attached directly to the effector(s) or through a peptides, and/or in combination with various antibiotic (e.g., linker. Where the targeting moiety and the effector comprise antibacterial) agents in various cleaning and/or sterilization peptides the chimeric moiety can be a fusion protein. formulations for use in the home, workplace, clinic, or hos Targeting Moieties. pital. 55 In various embodiments this invention provides targeting In certain embodiments the antimicrobial peptides moieties that preferentially and/or specifically bind to a described herein are attached to one or more targeting moi microorganism (e.g., a bacterium, a fungus, a yeast, etc.). One eties to specifically and/or to preferentially deliver the or more such targeting moieties can be attached to one or peptide(s) to a target (e.g. a target microorganism, biofilm, more effectors to provide chimeric moieties that are capable bacterial film, particular tissue, etc.). 60 of delivering the effector(s) to a target (e.g., a bacterium, a Other possible uses of the targeting and/or antimicrobial fungus, a yeast, a biofilm comprising the bacterium or fungus peptides disclosed herein include, but are not limited to bio or yeast, etc.). film dispersal, biofilm retention, biofilm formation, anti-bio In various embodiments, targeting moieties include, but film formation, cell agglutination, induction of motility or are not limited to peptides that preferentially bind particular change in motility type, chemoattractant or chemorepellent, 65 microorganisms (e.g., bacteria, fungi, yeasts, protozoa, algae, extracellular signal for sporogenesis or other morphological viruses, etc.) or groups of Such microorganisms, antibodies change, induction or inhibition of virulence gene expression, that bind particular microorganisms or groups of microorgan US 8,389,679 B2 21 22 isms, receptor ligands that bind particular microorganisms or targeting peptide. Typically the targeting peptides bind par groups of microorganisms, porphyrins (e.g., metalloporphy- ticular bacteria, and/or fungi, and/or yeasts, and/or algae, rins), lectins that bind particular microorganisms or groups of and/or viruses and/or bind particular groups of bacteria, and/ microorganisms, and the like. As indicated, it will be appre- or groups of fungi, and/or groups of yeasts, and/or groups of ciated that references to microorganisms or groups of micro- 5 algae. The targeting peptides provided can be used to effec organism include bacteria or groups of bacteria, viruses or tively deliver one or more effectors to or into a target micro groups of viruses, yeasts or groups of yeasts, protozoa or organism. Illustrative targeting peptides include, but are not groups of protozoa, viruses or groups of viruses, and the like. limited to the targeting peptides found in Table 2. Targeting Peptides. Other Suitable targeting peptides include the peptides that In certain embodiments the chimeric constructs described 10 have been identified as binding to particular target organisms herein comprise a targeting moiety that is or comprises a as shown in Table 3 and/or Table 4. TABLE 3 Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO:

1T-1 S. mutans YWNYNOSFNSGW 67

1T-2 S. mutans NIFEYFILE 68 S. sanguinis S. gordonii S. mitis S. oralis V. atypica Lactobacillus casei Saliva - derived biofilms

1T-3 S. mutans WLGIAGGLDAYGELWGGN 69 S. gordonii

1T-4 S. mutans LDAYGELWGGN 70 S. gordonii S. sanguinis S. oralis V. atypica L. casei

T- S. mutans GPIAGAAIGWDLGAISGAGL 71. S. sanguinis GWANFCO

T-6 S. mutans KFINGVLSOFVLERK 72

T-7 Myxococcus xanthus SORIIEPVKSPOPYPGFSVS 73

T-8 M. Xanthus FSWAACGEORAVTFWLLIEDLI 74

T-9 M. Xanthus WAWAESPRCWSTRSNIHALAF 7s RWEWAALT

T-1 O M. xanthus SPAGLPGDGDEA 76

T-11 S. mutans RISE 77 S. epidermidis P. aeruginosa

T-12 Corynebacterium FGNIFKGLKDWIETIWKWTAAK 78 xerosis Corynebacterium striatum S. epidermidis S. mutans

1T-13 S. aureus FRSPCINNNSLOPPGVYPAR 79 S. epidermidis P. aeruginosa

1T-14. S. mutans ALAGLAGLISGK 8O S. aureus S. epidermidis C. Xerosis

1T-15 S. militars DVILRVEAQ 81

1T-16 P. aeruginosa IDMR 82

1T-17 S. militars INNAIWYIS 83 US 8,389,679 B2 23 24 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO:

1T-18 eS YSKTLHFAD 84 epidermidis striatum aeruginosa

eS PGAFRNPOMPRG 85 epidermidis aeruginosa

initas PALWDLSNKEAWWAWLDDHS 86 aeruginosa

initas YWEEAWRAALKKEARISTEDTP 87 aeruginosa WNLPSFDC

epidermidis WPLDDGTRRPEWARNRDKDRED 88 aeruginosa

initas PALWDLSNKEAWWAWLDDHS 89 i. aeruginosa P. aeruginosa EEAEEKLAEWSQAVKRLVR 9 O

eS WGLDWSWLWLFFGLOLLSVILLG 91 epidermidis AMIR xerosis striatum aeruginosa

1T-26 S. initas LTILPTTFFAIIWPILAWAFIAYSG 92 S. eS FKIKGIVEHKDOW S. epidermidis Corynebacterium lieikeium C. xerosis C. striatum P aeruginosa

1T-27 initas ALFWSLEOFLVVVAKSVFALCH 93 eS SGTLS epidermidis lieikeium xerosis striatum aeruginosa

1T-28 P. aeruginosa WSRDEAMEFIDREWTTLOPAG 94 KSHA

1T-29 initas GSWIKKRRKRMSKKKHRKMLR 95 eS RTRVORRKLGK epidermidis lieikeium xerosis striatum aeruginosa

eS GKAKPYOVROVLRAVDKLETR 96 epidermidis RKKGGR xerosis striatum aeruginosa

1T-31 initas NATGTDIGEWTLTLGRFS 97 i. aeruginosa

S. initas WSFLAGWLCLGLAAWRLGNA 98

eS VRTL TILVIFIFNYLKSISYKLKO 99 epidermidis PFENNLAOSMISI lieikeium xerosis striatum aeruginosa US 8,389,679 B2 25 26 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO:

1T-34 eS AFWLNILLTLLGYIPGIWHAWYI 1OO epidermidis IAKR lieikeium xerosis striatum aeruginosa

P. aeruginosa EICLTLWFPIRGSYSEAAKFPWPI 1O1 HIWEDGTWELPK

1T-36 eS WYRHLRFIDGKLWEIRLERK 1O2 epidermidis lieikeium xerosis striatum aeruginosa

1T-37 initas YIWGALWILAWAGLIYSMLRKA 103 eleS epidermidis lieikeium xerosis striatum aeruginosa

1T-38 initas WMFWLTRGRSPRPMIPAY 104 eleS epidermidis lieikeium xerosis striatum aeruginosa

1T-39 initas FGFCVWMYOLLAGPPGPPA 105 i. aeruginosa

1T - 4 O S. initas ORVSLWSEVEHEFR 106 P. aeruginosa

1T - 41 initas KRGSKIWIAIAWWLIWLAGWWWW 1. Of eS epidermidis lieikeium striatum aeruginosa

1T - 42 eS TWLDWISLALATGLFWYLLWA 108 epidermidis LLRADRA. xerosis striatum aeruginosa

1T - 43 lieikium DRCLSWLSWSPPKWSPLI 109 aeruginosa

1T-44 initas DPALADFAAGMRAQVRT 11 O eS epidermidis lieikeium striatum aeruginosa

1T-45 eS WTKPSFTDLRLGFEWTLYFANR 111 epidermidis striatum aeruginosa

1T-46 eS FSFKORVMFRKEVERLR 112 epidermidis lieikeium xerosis striatum aeruginosa US 8,389,679 B2 27 28 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO:

1T-47 S. militars WIKISWPGOVOMLIP 113 S. epidermidis P. aeruginosa

1T-48 S. aureus KLOWHHGRATHTLLLQPPLCA 114 S. epidermidis PGTIR C. jelikelium C. Xerosis C. striatum P. aeruginosa

1T-49 S. aires SLVRIHDOOPWVTRGAFIDAAR 115 S. epidermidis TCS C. jelikelium P. aeruginosa 1T-50 P. aeruginosa HSDEPIPNILFKSDSWH 116

1T-51 S. aureus GKPKRMPAEFIDGYGOALLAGA 117 P. aeruginosa

1T-52 S. aureus DEYPAKLPLSDKGATEPRRH 118 C. Xerosis P. aeruginosa 1T-53 P. aeruginosa SDILAEMFEKGELOTLVKDAA 119 AKANA

1T-54 S. epidermidis RWVSCNPSWRIO 12 O C. Xerosis C. striatum P. aeruginosa

T-55 C. xerosis NHKTLKEWKAKWGPEAVESW 21 P. aeruginosa ATLIG

T-56 C. xerosis LALIGAGIWMIRKG 22 P. aeruginosa

T-57 P. aeruginosa RLEYRRLETOWEENPESGRRPM 23 RG

T-58 P. aeruginosa CDDLHALERAGKLDALISA 24

T-59 S. aires AWGNNLGKDNDSGHRGKKHR 25 S. epidermidis KHKHR P. aeruginosa

T- 6 O S. aureus YLTSLGLDAAEQAOGLLTILKG 26 S. epidermidis C. jelikelium C. striatum P. aeruginosa

1T - 61 P. aeruginosa HATLLPAVREAISROLLPALVP 127 RG

1T-62 S. epidermidis GCKGCAORDPCAEPEPYFRLR 128 P. aeruginosa

1T - 63 S. aureus EPLILKELWRNLFLFCYARALR 129 S. epidermidis C. jelikelium C. Xerosis C. striatum P. aeruginosa

1T-64 S. aureus OTWHHIHMHVLGOROMHWPPG 13 O S. epidermidis C. jelikelium C. Xerosis C. striatum P. aeruginosa US 8,389,679 B2 29 30 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO:

1T - 65 S. militars HARAAWGWAELPROGAAWEWEL 131 S. aureus IAAWRP S. epidermidis C. jelikelium C. Xerosis C. striatum P. aeruginosa

1T - 66 S. militars DTDCLSRAYAORIDELDKOYA 132 S. aureus GIDKPL S. epidermidis C. jelikelium C. Xerosis C. striatum P. aeruginosa

1T - 67 S. aires GORORLTCGRVSGCSEGPSREA 133 S. epidermidis AR C. jelikelium C. Xerosis C. striatum P. aeruginosa

1T - 68 S. militars GGTKEIWYORG 134 S. aureus C. jelikelium C. Xerosis C. striatum P. aeruginosa

T-69 S. militas ILSQEADRKKLF 35 P. aeruginosa

T-7 O S aires NROAOGERAHGEQOG 36 C. jelikelium P. aeruginosa T-71 P. aeruginosa KIDTNOWPPNKEG 37

T-72 P. aeruginosa EPTDGWACKER 38

T-73 Streptococcus GWWEELLHETILSKFKITKALE 39 pneumoniae LPIQL

T-74. S. pneumoniae DIDWGRKISCAAGWAYGAIDG 4 O CATTV

T-75 S. pneumoniae GVARGLOLGIKTRTOWGAATG 41 AA

T-76 S. pneumoniae EMRLSKFFRDFILWRKK 42

T-77 S. pneumoniae EMRISRIILDFLFLRKK 43

T-78 S. pneumoniae FFKTIFWLILGALGWAAGLYIEK 44 NYIDK

T-79 S. pneumoniae FGTPWSITNEWKKNFNDRPDF 45 DSDRRRY

T-80 S. pneumoniae GGNLGPGFGWIIP 46

T-81 S. pneumoniae AIATGLDIWDGKFDGYLWA 47

T-82 S. pneumoniae FGWGWGIALFMAGYAIGKDLR 48 KKFGKSC

T-83 S. pneumoniae OKPRKNETFIGYIORYDIDGNG 49 YOSLPCPON T-84 S. pneumoniae FRKKRYGLSILLWLNAFTNLWN SO SIHAFYMTLF US 8,389,679 B2 31 32 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO :

A. naeslundii, F. nucleatum, WMASLTWRMRAASASLPTHSR 151 P. gingivalis TDA S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

S. mitis, S. oralis, S. salivarious 52

S. mitis, S. mutans, S. oralis EAVGODLVDAHHP 53

Unanalyzed GRLWLEITADEWKALGEALAN 54 AKI

S. mitis, S. mutans HEDDKRRGMSVEVLGFEVWOH 55 EE

S. gordonii, S. mitis, S. mutans, RNVIGOVL 56 S. oralis, S. sanguinis

S. mitis, S. mutans, S. oralis, TSWRPGAAGAAWPAGAAGAA f S. sanguinis GAGWRWP

S. mitis, S. mutans GODEGORRAGWGEGQGWDG 58

S. epidermidis, S. gordonii, AMRSVNOA 59 S. mitis, S. mutans, S. oralis, S. sanguinis

S. mitis, S. mutans, S. oralis DOVAHSGDMLVOARRRDS 6 O

S. gordonii, S. mitis, S. mutans, 61 S. oralis, S. sanguinis

S. gordonii, S. mitis, S. mutans, WAGACAQPFGGO 62 S. oralis, S. sanguinis

A. naeslundii, F. nucleatum, GWAERNLDRITWAWAIIWTITIW 63 P. gingivalis GIGLWAKLG S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-98 A. naeslundii, F. nucleatum, WRSAKAWKALTAAGYTGELWN 164 P. gingivalis WSGGMKAWLGO S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-99 S. gordonii, S. mitis, S. mutans, MKAWLGO 1.65 S. oralis, S. sanguinis

1T-1 OO S. gordonii, S. mitis, S. mutans LDPLEPRIAPPGDRSHOGAPAC 166 HRDPLRGRSARDAER

1T-101 A. naeslundii, P. gingivalis RLRWGRATDLPLTSFAWGVWR 167 S. epidermidis, NLPDAPAH S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-102 A. naeslundii, F. nucleatum, WKRLWPARILAGHSRRRMRW 168 P. gingivalis MWWWRYFAAT S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-103 A. naeslundii, F. nucleatum, AQFYEAIITGYALGAGORIGOL 169 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis US 8,389,679 B2 33 34 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO :

1T-104 S. mitis RAVAAHLQGRHHGHQWRROR 17 O HGOR

1T-105 S. epidermidis, S. gordonii, GEGLPPPWLHLPPPRMSGR 171 S. mitis, S. mutans, S. oralis

1T-106 S. gordonii, S. mitis, S. mutans, DALRRSRSOGRRHR 172 S. oralis, S. salivarious

1T-1. Of A. naeslundiis. epidermidis, SPWPRFTAWGGWSRGSP 173 S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-108 S. gordonii, S. mitis, S. mutans, WGPLGPERPLW. 174 S. oralis, S. salivarious, S. sanguinis

1T-109 A. naeslundiis. epidermidis, WTTNVROGAGS 17s S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-110 A. naeslundii, P. gingivalis LAAKTAWCWGRAFM 176 S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-111 A. naeslundii, F. nucleatum, GRLSRREEDPATSIILLRGAYR 177 P. gingivalis MAWF S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-112 S. gordonii SDNDGKLILGTSQ 178

1T-113 S. mitis HGAHORTGORLHHHRGRTVSG 179 CRONPVAGVDPDEHR

1T-114 A. naeslundii, P. gingivalis ROAPGPGLVTITAACSAPGSRSR 18O S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-115 A. naeslundii, F. nucleatum, LLIERFSNHH 181 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-116 A. naeslundii, P. gingivalis MILHRRRDR 182 S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-117 S. mutans GPGWWGPAPFSRLPAHALNL 183

1T-118 A. naeslundii, F. nucleatum, TASPPAPSDQGLRTAFPATLLIA 184 P. gingivalis LAALARISR S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-119 S. gordonii, S. mitis, S. mutans, SPATOKAPTRAOPSRAPVODC 185 S. oralis GDGRPTAAPDDWERLSPR

1T-120 A. naeslundii, F. nucleatum, DWRDRWDLAGADLCAAHATR 186 P. gingivalis S. epidermidis, US 8,389,679 B2 35 36 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO : S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

S. gordonii, S. mitis, S. mutans, FAKETGFGIGGAQEGWWIIADI 87 S. oralis, S. salivarious, YGPNPF S. sanguinis

S. mitis GAIPDPWTHRVDWEEDHOTRP 88 SR

S. gordonii LVRRNAVAGRSDGLAGAEOLD 89 LVRLQGVL

S. mitis, S. mutans, S. oralis LFDERNKIA 9 O

S. epidermidis, S. gordonii, DAITGGNPPLSDTDGLRP 91 S. mutans, S. oralis

S. gordonii, S. mitis, S. mutans OGLARPWLRRIPL 92

A. naeslundii, F. nucleatum, YDPWPKRKNKNSEGKREE 93 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-128 A. naeslundii, P. gingivalis SGSAIRMLEIATKMLKR 194 S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-129 A. naeslundii, P. gingivalis YDKYIKYLSIOPPFIWYFI 195 S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-130 A. naeslundii, F. nucleatum, OKIIDMSKFLPSLILFIMIVWIYI 196 P. gingivalis GKSIGGYSAIWSSIMLELDTWLY S. epidermidis, NKKIFFIYK S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-131 A. naeslundii, F. nucleatum, DEWWKMLGI 197 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-132 A. naeslundii, F. nucleatum, YSKKLFEYFYFIIFILIRYLIFYKI 198 P. gingivalis IONKNYYINNIAYN S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-133 A. naeslundii, P. gingivalis YFIKDDNEALSKDWEWIGNDL 199 S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-134 A. naeslundii, F. nucleatum, SRLWREIKKKCRKS 2OO P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-135 A. naeslundii, P. gingivalis FESLLPOATKKIVNNKGSKINKIF S. epidermidis, S. gordonii, S. mitis, S. mutans, US 8,389,679 B2 37 38 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO : S. oralis, S. salivarious, S. sanguinis

1T-136 A. naeslundii, F. nucleatum, ELLTOIRLALLYSWNEW 2O2 P. gingivalis, S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-137 A. naeslundii, F. nucleatum, PLNFYRAWKENRLPLSEKNIND P. gingivalis FTNIKLKVSPKLINLLOESSIFY S. epidermidis, NFSPKKRNTN S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-138 A. naeslundii, F. nucleatum, YPNEYCIFLENLSLEELKEIKAI 2O4. P. gingivalis NGETLNLEEIINERKNLKD S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-139 A. naeslundiiS. gordonii, AWAGAAWGALLGNDARSTAW 2O5 S. mitis, S. mutans, S. oralis GAAIGGAL.GAGAGELTKNK

1T-14 O A. naeslundii, F. nucleatum, IKGTIAFWGEDYWEIRWDKGWK P. gingivalis LTFRKSAIANVINNNOO S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-141 F. nucleatum, P. gingivalis KKFIILLFILVOGLIFSATKTLSD S. epidermidis, IIAL S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-142 A. naeslundii, F. nucleatum, FTOGIKRIVLKRLKED P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-143 A. naeslundii, F. nucleatum, MPKRHYYKLEAKALOFGLPFA 209 P. gingivalis YSPIOLLK S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-144 A. naeslundii, F. nucleatum, IIELHPKSWTODWRCSFL 21 O P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-145 S. mitis, S. mutans, S. oralis WEAGKRNISLENIEKISKGLGISI 211 SELFKYIEEGEDKIG

1T-146 A. naeslundii, F. nucleatum, RNSADNOTKIDKIRIDISLWDE 212 P. gingivalis, HLNIWKOGK T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-147 A. naeslundii, F. nucleatum, GWENRRFYERDWSKWSMMTSE 213 P. gingivalis, AWAPRGGSK T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-148 A. naeslundii, F. nucleatum, IWELDDTTILERALISMILGEANA 214 P. gingivalis, US 8,389,679 B2 39 40 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO: T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-149 A. naeslundii, F. nucleatum, SWRAWKPIDETWARHFPGDFIWN 215 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-150 A. naeslundii, F. nucleatum, YINRRLKKAFSDADIKEAPAEF 216 P. gingivalis, YEELRRVOYV T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-151 A. naeslundii, F. nucleatum, SWRAWKPIDEIWAWHFPGDFIWN 217 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-152 A. naeslundii, F. nucleatum, YWSADESAYNHIWTDDIPLADR 218 P. gingivalis RIEAVOO S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-153 A. naeslundii, F. nucleatum, YIACPGYFY 219 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-154 P. gingivalis YFSFLEIWGMARR 22 O

1T-155 A. naeslundii, F. nucleatum, LKLAFGVYPFOAMSOSDTAVS 221 P. gingivalis ERNWLWR S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-156 A. naeslundii, F. nucleatum, GRFOISIRGEEKSKWKVOGKGT 222 P. gingivalis, FTDRNTT T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-157 A. naeslundii, F. nucleatum, RRFRKTTENREKSKNKKAWLG 223 P. gingivalis, LSTTSTASY T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-158 A. naeslundii, F. nucleatum, WENKPSPLGSIKKLQGLWYRLI 224 P. gingivalis GYRHFWW S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-159 P. gingivalis IFSLHHFALICSEMGTFAWSKRA 225 KYKWEWL

1T-16O A. naeslundii, F. nucleatum, AQYKYINKLLN 226 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-161 A. naeslundii, F. nucleatum, NKVLOVEVMWDGSVVGRPAG 227 P. gingivalis WISIKSSKKG US 8,389,679 B2 41 42 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO: S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-162 A. naeslundii, F. nucleatum, OKAKEESDRKAAVSYNGFHRV 228 P. gingivalis, NWWSIPK T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-163 A. naeslundii, F. nucleatum, MENILIYIPMWLSPFGSGILLFLG 229 P. gingivalis KDRRYML S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-164 A. naeslundii, F. nucleatum, KKSHSOGKRKLKDLNSAYKID 23 O P. gingivalis NOLHYALR S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-165 A. naeslundii, F. nucleatum, CYDSFDFSIFWTFANRMIKLSWGS 231 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-166 A. naeslundii, F. nucleatum, AOSAGOIKRKSKVRIHV 232 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-167 A. naeslundii, F. nucleatum, SRMSEHSPAGLWFEWGPMDKG 233 P. gingivalis SFIILDSYHPTWKK S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-168 A. naeslundii, F. nucleatum, ELHRIMSTEKIGAWTKMNFDTA 234 P. gingivalis PIMSILPIDIYPKEWGIGS S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-169 A. naeslundii, F. nucleatum, FARVRRLHONRILTOPLTNLKY 235 P. gingivalis CLROPIYSD S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-17O P. gingivalis AYGKWFSMDIMLSENDKLIWLR 236 ISHHSAWH

1T-171 A. naeslundii, F. nucleatum, SWRAWKPIDKTWARHFPGDFIWN 237 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-172 A. naeslundii, F. nucleatum, FEGLKNLLGDDII 238 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, US 8,389,679 B2 43 44 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO: S. oralis, S. salivarious, S. sanguinis

1T-173 A. naeslundii, F. nucleatum, LFRKEDOEHVLL 239 P. gingivalis S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-174 A. naeslundii, F. nucleatum, SGGSDTDGSSSGEPGSHSGDL 24 O P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-175 A. naeslundii, F. nucleatum, GEPGSHSGDL 241 P. gingivalis, S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-176 A. naeslundii, P. gingivalis PWGDIMSGFLRGANOPRFLLDH 242 S. epidermidis, ISFGS S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-177 P. gingivalis.S. gordonii, GTNWPTOILGYSREERFDYEPA 243 S. mitis, S. mutans, S. oralis, PEOR S. salivarious, S. sanguinis 1T-178 A. naeslundii, F. nucleatum, LLASHPERISLGWFFWYRWLHL 244 P. gingivalis LLENT S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-179 A. naeslundii, F. nucleatum, TCYPLIORKTDRAYEA 245 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-180 A. naeslundii, F. nucleatum, WWFGGGDRLW 246 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-181 A. naeslundii, F. nucleatum, YGKESDP 247 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-182 A. naeslundii, F. nucleatum, LTASICROWNDNSTPYOR 248 P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-183 A. naeslundii, F. nucleatum, PLRSFWAEKAEHAFRVWRIADF 249 P. gingivaliss. DFGHS epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-184 A. naeslundii, F. nucleatum, ALLVLNLLLMOFFFGKNM 25 O P. gingivalis, T. denticolas gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis US 8,389,679 B2 45 46 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO :

1T-185 naeslundii, F. nucleatum, HYHFLLEFGFHKGDYLE 251 gingivalis, denticolas. gordonii, mitis, S. mutans, S. oralis, salivarious, S. sanguinis

1T-186 S. sanguinis LAKKNOALREEISROKSK 252

1T-187 S. sanguinis RAGRIKKLSOKEAEPFEN 253

1T-188 S. sanguinis HRKDWYKK 254

1T-189 F. nucleatum, S. sanguinis FIRSKLRRWDFSGWRRGNKHFL 255 LDKLLITLWK

1T-190 A. naeslundii, F. nucleatum, IOIIVNAFVEKDKTGAVIEWLYA 256 P. gingivaliss. SNNHEKWKAKYEELWAIS epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-191 F. nucleatum, S. sanguinis SALFYDTLAAIWISIAGWDARW 257 GH

1T-192 S. sanguinis ILWLLALOWELDSKFOY 258

1T-193 S. sanguinis LMIFDKHANLKYKYGNRSFGW 259 EAIM

1T-194 F. nucleatum, S. sanguinis LAGATLWTPYCWGWGLIRSH 26 O 1T-19s Unanalyzed AASGFTYCASNGWWHPY 261

1T-196 F. nucleatum, S. sanguinis KPEKEKLDTNTLMKWWNKALS 262 LFDRILLIKFGA.

1T-197 A. naeslundii, F. nucleatum, TEILNFLITWCADRENWKIKHG 263 P. gingivaliss. LSDSWLLIFFARFTGAEYW epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-198 P. gingivaliss. MPWSKKRYMLSSAYATALGIC 264 epidermidis, S. gordonii, YGOVATDEKESEITAIPDLLDY S. mitis, S. mutans, S. oralis, LSWEEYLL S. sanguinis

1T-199 S. sanguinis RAGRIKKLSOKEAEPFEN 265 1T-2OO A. naeslundii, F. nucleatum.S. MRFKRFDRDYALSGDNWFEWL 266 epidermidis, S. gordonii, TASCDVIERNLSYREMCGLMO S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

S. sanguinis KRKHENWIWAEEMRWIKN 267

A. naeslundii, F. nucleatum, LCRLEKLCKOFLRODKVVTYY 268 P. gingivaliss. LMLPYKRAIEAFYOELKERS epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

A. naeslundii, F. nucleatum, YPFCLATWDHLPEGLSWTDYER 269 P. gingivaliss. WORLWSOFLLNKEER epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

F. nucleatum, S. sanguinis KYLFLASKTKEYFKSHFREIMI 27 O DV US 8,389,679 B2 47 48 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO :

A. naeslundii, F. nucleatum, FISFWDCIONIEKIEKELLKIGIT 271 P. gingivaliss. DIOINQDAGWLY epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

S. sanguinis AGFAAGYSL 272 F. nucleatum, S. sanguinis SPLEKYGTGSMTALTFLLGCCL 273 LWLSKKSR

Unanalyzed KRKRWAILTLFLAGLGAWGIWL 274 ATF

T-209 F. nucleatum, S. sanguinis WSGAAWGAATFC 27s S. sanguinis SVGMGVIERGSFDFSASAILOK 276 RETKCLKNKPFT

S. sanguinis AEPIIKWTEG 277

S. sanguinis LLSALIKKLALIIFIG 278

S. sanguinis AYLLTCAAAGGMIGYGAATLD 279

S. sanguinis MIGYGAATLD 28O

S. sanguinis WCFKDISVFLSPFRGOEWLFCG 281 KAKHSLIYWIGT

S. sanguinis FFLNWIAIRIPHF 282

F. nucleatum, S. sanguinis MLSNWLSRSWWSPNWDIPNSMW 283 ILSPLLISISNYH

F. nucleatum, S. sanguinis KLIFAALGLWFLLIGLRDSRSK 284

S. sanguinis RNINWSATFITEKSLW 285

A. naeslundii, F. nucleatum, AILTFFMALLFTYLKEKAOILY 286 P. gingivaliss. WPLFLHLMFYFWTA epidermidis, S. gordonii, S. oralis, S. salivarious, S. sanguinis

1T-221 A. naeslundii, F. nucleatum, DIGRIIGKKGRTITAIRSIWYSWP 287 P. gingivaliss. TOGKKVRLVIDEK epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-222 F. nucleatum, S. sanguinis RIEASLISAIMFSMFNAIVKFLOK 288

1T-223 A. naeslundii, F. nucleatum, NOKMEINSMTSEKEKMLAGHF 289 P. gingivaliss. HNEANFAWIFKYSLFYNFF epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-224 A. naeslundii, F. nucleatum, WHLFSFWKLIYYDIMKYSIEEK 29 O P. gingivaliss. WFFESPWGEIIQ epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-225 A. naeslundii, F. nucleatum, RRSLGNSASFAEWIEYIRYLHYI 291 P. gingivaliss. IRVOFIHFFSKNKKI epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis US 8,389,679 B2 49 50 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO : 1T-226 A. naeslundii, F. nucleatums. KLOEKOIDRNFERVSGYSTYRA 292 epidermidis, WOAAKAKEKGFISLEN S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-227 S. sanguinis RFEOFFADHYPFW 293

1T-228 A. naeslundii, F. nucleatum, IFKLFEEHILLYLLDAFYYSKIFR 294 P. gingivaliss. RLKOGLYRRKEOPYTODLFRM epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-229 S. gordonii, S. oralis, S. sanguinis LLINYWKWNMSY 295

1T-23 O A. naeslundii, F. nucleatum, EFLEKFKVLKOPRKANNISKNR 296 P. gingivaliss. WAMIFLTIHKSRGFLSSPY epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-231 S. gordonii, S. mitis, S. mutans, FDFLCSPDSSR 297 S. oralis, S. salivarious

1T-232 S. sanguinis AYSLTFONPNDNLTDEEVAKY 298 MEKITKALTEKIGAEWR

1T-233 A. naeslundii, P. gingivaliss. TDOELEHLIVTELESKRLDFTYS 299 epidermidis, KDITEFFDEAFPEYDONY S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-234 A. naeslundii, F. nucleatum, DNFYLILKMEERGKSKKTSOTR P. gingivaliss. GFRAFFDIIRKKIKKEDGK epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-235 S. sanguinis GWLSDDFWLKSAIPLLKKRLA. 3O1 KWNETL

1T-236 A. naeslundii, F. nucleatum, PVOKALHVVSAYATDLGICYD P. gingivaliss. OVWTVMIREVKTOLYOIY epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-237 S. sanguinis EDPWPNHFTLRRNKKEKPSKS

1T-238 A. naeslundii, F. nucleatum, IFNRRKFFOYFGLSKEAMVEHI P. gingivaliss. QPFILDIWOIHLF epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-239 A. naeslundiiS. gordonii, ADDLLNKRLTDLIMENAETWK 305 S. mitis, S. mutans, S. oralis, TIDLDNSD S. sanguinis

1T-24 O A. naeslundii, F. nucleatum, WILGNGISNIAQTLGOLPNIAW 3 O 6 P. gingivaliss. WWIYMWLIAALLEESNWC epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-241 S. sanguinis TOKTYLHIIRELENODIDLIMRS 3. Of LTSLT US 8,389,679 B2 51 52 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO : 1T-242 F. nucleatum, S. sanguinis KOVONTTLIICGTVLLGILFKSY LKSQKSW

1T-243 A. naeslundii, P. gingivaliss. SENIARFAAAFENEOVWSYAR 309 epidermidis, WFRRSWRGSGSSSRF S. gordonii, S. mitis, S. mutants, S. oralis, S. salivarious, S. sanguinis

1T-244 A. naeslundii, P. gingivalis MTWAEIGAIWGATIGSFYIPNPW 31 O S. epidermidis, IWPFRVR S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-245 F. nucleatum, S. sanguinis IIGGISGAGWGIASFC 311

1T-246 S. sanguinis ISGAGWGIASFC 312

1T-247 A. naeslundii, F. nucleatum, LSISORTDRVIVMDKGKIIEEGT 313 P. gingivalis HSELIAANGFYHHLFNK S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

T-248 S. sanguinis IGGALNSCG

T-249 F. nucleatum, S. sanguinis WFSVLKHTTWPTRKOSWHDFIS ILEYSAFFALWIFIFDKLLTLGLA ELLKRF

T-250 S. mitis, S. mutans, S. oralis LVOGDTILIENHVGTPVKDDGK DCLIIREADWLAWWND

T-251 S. mitis, S. oralis, S. sanguinis LVMNDETIYLFTYENGOISYEE DKRDCSKNW

T-252 F. nucleatum, S. sanguinis MKKNLKRFYALWLGFIIGCLFW SILIFIGY

T-253 A. naeslundii, F. nucleatum, KTKESLTOOEKKFLKDYDRKS P. gingivalis LHHFRDILTYCFILDKLTNK S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-254 S. sanguinis RFLKDELSVSWRLOEKSIEALPF 32O RTKIEIEIESDNOIKTL

1T-255 A. naeslundii, F. nucleatum, LFIWEYKDKASWPGEIDNTYWE 321 P. gingivalis SYTYSDILTEKTLIRYFD S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-256 S. sanguinis KGKSLMPLLKOINQWGKLYL 322

1T-27 A. naeslundii, F. nucleatum, IILAKAADLAEIERIISEDPFKIN 323 P. gingivalis EIANYDIIEFCPTKSSKAFEKWLK S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-258 A. naeslundii, F. nucleatum, TINIDDKWLDYLKKINSKAITID 324 P. gingivalis, LIGCAS T. denticola, S. mitis, S. mutans, S. oralis

1T-259 F. nucleatum, P. gingivalis, EKLKKILLKLAWCGKAWYTL 3.25 T. denticola, S. mitis, S. mutans, S. oralis, S. sanguinis US 8,389,679 B2 53 54 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO :

1T-260 A. naeslundii, P. gingivalis NILYFIHDENOWEPOKAEIFRG 326 S. epidermidis, SIKHCAWLSS S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis

1T-261 F. nucleatum S. mutans, SFEKNKIENNLKIAQAYIYIKPK 327 S. oralis S. sanguinis PRICOA

1T-262 A. naeslundii, F. nucleatum, LSLPLIWLTKSI 328 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-263 A. naeslundii, F. nucleatum, FIAWSFTGNPATFKLWIGCKADN 329 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. oralis, S. salivarious, S. sanguinis

1T-264 S. sanguinis LEGKFYMAEDFDKTPECFKDYW 33 O

1T-265 A. naeslundii, F. nucleatum, GMFENLLMINFOIMNDLKIEIV 331 P. gingivalis WKDRICAW S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-266 S. sanguinis RAGTWLWWDEIR 332

1T-267 A. naeslundii, F. nucleatum, RIKEERKNRSYKFFIWRLFDEK 333 P. gingivalis, TGFI T. denticola, S. mitis, S. mutans, S. oralis S. sanguinis

1T-268 F. nucleatum S. mutans, PITPKKEKCGLGTYAPKNPWFS 334 S. oralis S. sanguinis KSRW

1T-269 F. nucleatum S. mutans, PLYWAAWEKINTAKKH 335 S. oralis S. sanguinis

1T-270 F. nucleatum S. mutans, WHEFDIOKILONR 336 S. oralis S. sanguinis

1T-271 A. naeslundii, F. nucleatum, FLIOKFLLIKTFPPYRKKYWWIV 337 P. gingivalis SOTGTA S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-272 F. nucleatum S. mutans, QL.APIDKOLKAVKKIAFYESES 338 S. oralis S. sanguinis TAAKAWTWA

1T-273 F. nucleatum, P. gingivalis, YNEPNYKWLESYKIYKORCED 339 T. denticola, RTGMYYTEET S. mitis, S. mutans, S. oralis

1T-274 F. nucleatum S. mutans, ETTTEINAIKLHRIKORSPOGTR 34 O S. oralis S. sanguinis RVN

A. naeslundii, F. nucleatum, OVLKNFSISRRYKINNPFFKILL 341 P. gingivalis, FIOLRTL T. denticola, S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-276 A. naeslundii, F. nucleatum, ILTLLILGSIGFFILKIKLKLGRF 342 P. gingivalis S. epidermidis, US 8,389,679 B2 55 56 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO: S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis 1T-277 A. naeslundii, F. nucleatum, IYYMRFWNKPLEKTFFK 343 P. gingivalis, T. denticola S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-278 A. naeslundii, F. nucleatum, SINSSAGIOPHCLSSSFVLRTKH 344 P. gingivalis, CFY S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-279 A. naeslundii, F. nucleatum, FWLRTKHCFY 345 P. gingivalis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-280 A. naeslundii, F. nucleatum, TNNKNKWIIKAIKFKNKDFINL 346 P. gingivalis, DLFIYRR T. denticola S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-281 A. naeslundii, F. nucleatum, KYEKLTKENLFIRNSGNMCWFI 347 P. gingivalis YFLFFG S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-282 F. nucleatum, P. gingivalis, ISLWFPAYT 348 S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-283 A. naeslundii, F. nucleatum, LCTKLEDKORGRIPAELFIISPIK 349 P. gingivalis, ILERNDAL T. denticola, S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-284 A. naeslundii, F. nucleatum, FOYYFSLKRV 350 P. gingivalis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-285 A. naeslundii, F. nucleatum, FFPYYLADFYKOLKFLNEYOT 351 P. gingivalis, KNKDKWWEFK S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-286 S. sanguinis LGFFNNKADLWKADTERDNRM 352 SSLKIKDL

1T-287 P. gingivalis, T. denticola KGYPLPFOYRLNNH 353 S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-288 F. nucleatum, S. gordonii, RWWGGEPSADIYLSAKDTKT 3.54 S. salivarious, S. sanguinis

1T-289 F. nucleatum, P. gingivalis, EPSADIYLSAKDTKT 355 S. gordonii, S. mitis, S. mutans, S. oralis, S. sanguinis US 8,389,679 B2 57 58 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID ID Target (s) Targeting Peptide Sequence NO:

1T-290 A. naeslundii, F. nucleatum, IINOLNLILLRLMEILIL 356 P. gingivalis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-291 A. naeslundii, F. nucleatum, DMKIIKLYIKILSFLFIKYCNKK 357 P. gingivalis, LNSWKLKA. T. denticola, S. mitis, S. mutans, S. oralis

1T-292 A. naeslundii, F. nucleatum, IINOLNLILLRLMEILIL 358 P. gingivalis S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-293 A. naeslundii, F. nucleatum, HWEDCFLLSNARTTAIHGRANP 359 P. gingivalis ARGEPRTRSE S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-294 T. denticola YDKIADGWFKIGKRGVL 360

1T-295 S. mitis, S. salivarious, KYKLKKIIL 361 S. sanguinis

1T-296 A. naeslundii, F. nucleatum, EYSOOSFKAKPCSERGVLSP 362 P. gingivalis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-297 A. naeslundii, F. nucleatum, RSLRLNNALTKLPKLWYNRIKE 363 T. denticola, AFYAYNDYDK S. mitis, S. mutans, S. oralis 1T-298 A. naeslundii, F. nucleatum, ILNKKPKLPLWKLGKNYFRRF 364 P. gingivalis, YWLPTFLA T. denticola S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-299 A. naeslundii, F. nucleatum SMLTSFLRSKNTRSLKMYKDW 365 S. epidermidis, HF S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-300 A. naeslundii, F. nucleatum, PLIISKAQIKMSGDILGSCFKLF 366 P. gingivalis YLRPFF S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis 1T-301 F. nucleatum, S. gordonii, SKLPRWLDASLKL 367 S. sanguinis 1T-3 O2 A. naeslundii, P. gingivalis IIILPKIYLWCKTV 368 S. epidermidis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis

1T-303 A. naeslundii, F. nucleatum, LDYENMDCKKRIRI 369 P. gingivalis, S. gordonii, S. mitis, S. mutans, S. oralis, S. salivarious, S. sanguinis US 8,389,679 B2 59 60 TABLE 3 - continued Illustrative list of novel targetinct peptides.

SEO ID D Target (s) Targeting Peptide Sequence NO: T-3 O4 P. gingivalis STAGEASRRTASEASRRTAAKL 37 O RG

TT-3 O5 F. nuclea tum ARNALNMRDWPWDAAIIGIIDG 3.71 MDEE

TT-3 O6 F. nuclea tum KILNEAEGKLLKWIEKNGEIDIE 372 EI

TT-3 Of F. nuclea tum NGDKKAKEELDKWDEWIKELN 373 IOF

TT-3 O8 F. nuclea tum GLVIIPNLIALIILFSQWROQTKD 374 YFSNPKLSSR

TT-3 O9 F. nuclea tum EPLPLTKYDKKDTEMKKWFKEI 375 LAGKWGYEKEEE

TT-31 O F. nuclea tum TKLKKNNKLLSAKKENTLHTK 376 DK

TT-311 S. mutans, S. sobrinus AIFDAMHNL 377

As described above, in certain embodiments of the present screening peptide libraries. For example, a phage display invention, the targeting moiety can comprise targeting pep peptide library can be screened against a target microbial tide capable of binding, specifically binding, or preferentially organism or a desired antigen or epitope thereof. Any peptide 30 identified through such screening can be used as a targeting binding to a microorganism, e.g., a target microbial organism. peptide for the target microbial organism. Illustrative addi In one embodiment, the targeting peptide be identified via tional targeting peptides are shown in Table 4. TABL E 4. Additional illustrative targetinct moieties. Targeting Moiety/ SEO ID Organism Structure/sequence NO

LPSB-1 RGLRRLGRRGLRRLGR 378

Phoo-1 KPWLPWLPWLPWL 379

LPSB-2 WLRIIRIAWLRIIRIA 38O

LPTG-1 LPETGGSGGSLPETG 381

C-1 RAHIRRAHIRR 382

ANION-1 DEDEDDEEDDDEEE 383

PHILIC-1 STMCGSTMCGSTMCG 384

SA5. 1/S. aureus WRLPLWLPSLNE 385

SA5.3/S. aureus ANYFLPPWLSSS 386 SA5.4/S. aureus SHPWNAORELSV 387 SA5.5/S. aureus SWSWGMRPMPRP 388

SA5.6/S. aureus WTPLHPSTNRPP 389

SA5.7/S. aureus SWSWGMKPSPRP 390

SA5.8/S. aureus SWSWGMKPSPRP 391

SA5.9/S. aureus SVPWGPYNESOP 392

SA5. 10/S. aureus WAPPLFRSSLFY 393

SA2.2/S. aureus WAPPXPXSSLFY 394

US 8,389,679 B2 63 64 TABLE 4 - continued Additional illustrative targetinct moieties. Targeting Moiety/ SEQ ID Organism Structure/sequence NO

Hi3/17 KORTSIRATEGCLPS 432

C.-E. coli peptide QEKIRVRLSA 433

Salivary Receptor OLKTADLPAGRDETTSFWLV* 434 Adhesion Fragment

S1 (Sushi frag.) GFKLKGMARISCLPNGOWSNFPPKCIRECAMVSS 435 (LPS binding)

S3 (Sushi frag.) HAEHKWKIGWEOKYCOFPOGTEVTYTCSGNYFLM 436 (LPS binding)

MArg. 1 AMDMYSIEDRYFGGYAPEWG 437 (Mycoplasma infected cell line binding peptide

BPI fragment 1 ASQQGTAALOKELKRIKPDYSDSFKIKH 438 (LPS binding) 6,376, 462

BPI fragment 2 SSOISMVPNVGLKFSISNANIKISGKWKAOKRFLK 439 (LPS binding) 6,376, 462

BPI fragment 3 WHVHISKSKVGWLIOLFHKKIESALRNK 44 O (LPS binding) 6,376, 462

LBP fragment 1 AAQEGLLALOSELLRITLPDFTGDLRIPH 441 (LPS binding) 6,376, 462

LBP fragment 2 HSALRPVPGOGLSLSISDSSIRVOGRWKVRKSFFK 442 (LPS binding) 6,376, 462

LBP fragment 3 WEVDMSGDLGWLLNLFHNOIESKFOKV 443 (LPS binding) 6,376, 462

B. anthracis spore ATYPLPIR 444 binding (WO/1999/O36 O81) Bacilius spore binding peptides of 5-12 amino acids containing the sequence 445 (WO/1999/O36 O81) Asn-His-Phe-Leu. peptides of 5-12 amino acids containing the sequence 446 Asn-His-Phe-Leu-Pro Thr-Ser-Glu-Asn-Val-Arg-Thr (TSQNVRT) 447 A peptide of formula Thr-Tyr-Pro-X-Pro-X-Arg 4 48 (TYPXPXR) where X is a Ile, Wall or Lieu. A peptide having the sequence TSQNVRT. 449 A peptide having the sequence TYPLPIR 450

LPS binding peptide 1 TFRRLKWK 451 (6,384, 188)

LPS BP 2 (6,384, 188) RWKVRKSFFKLO 452

LPS BP 3 (6,384, 188) KWKAOKRFLKMS 453

Pseudomonas pilin KCTSDODEOFIPKGCSK 454 binding peptide (5, 494, 672) Patents and patent publications disclosing the referenced antibodies are identified in the table.

In certain embodiments the targeting moieties can com target microbial organism, e.g., the cell Surface appendages prise other entities, particularly when utilized with an antimi Such as flagella and pili, and Surface exposed proteins, lipids crobial peptide as described, for example, in Table 2. Illus and polysaccharides of a target microbial organism. trative targeting moieties can include a polypeptide, a 65 Targeting Antibodies. peptide, a small molecule, a ligand, a receptor, an antibody, a In certain embodiments the targeting moieties can com protein, or portions thereof that specifically interact with a prise one or more antibodies that bind specifically or prefer US 8,389,679 B2 65 66 entially a microorganism or group of microorganisms (e.g., In certain embodiments the antibodies produced will be bacteria, fungi, yeasts, protozoa, viruses, algae, etc.). The monoclonal antibodies (“mabs'). The general method used antibodies are selected to bind an epitope characteristic or the for production of hybridomas secreting mAbs is well known particular target microorganism(s). In various embodiments (Kohler and Milstein (1975) Nature, 256:495 Such epitopes or antigens are typically is gram-positive or Antibody fragments, e.g. single chain antibodies (ScPV or gram-negative specific, or genus-specific, or species-specific, others), can also be produced/selected using phage display or strain specific and located on the Surface of a target micro and/or yeast display technology. The ability to express anti bial organism. The antibody that binds the epitope or antigen body fragments on the surface of viruses that infect bacteria can direct an anti-microbial peptide moiety or other effector (bacteriophage orphage) or yeasts makes it possible to isolate 10 a single binding antibody fragment, e.g., from a library of to the site. Furthermore, in certain embodiments the antibody greater than 10" nonbinding clones. To express antibody itself can provide anti-microbial activity in addition to the fragments on the Surface of phage (phage display) or yeast, an activity provided by effector moiety since the antibody may antibody fragment gene is inserted into the gene encoding a engage an immune system effector (e.g., a T-cell) and thereby phage surface protein (e.g., pIII) and the antibody fragment elicit an antibody-associated immune response, e.g., a 15 pIII fusion protein is displayed on the phage surface (McCaf humoral immune response. ferty et al. (1990) Nature, 348: 552-554; Hoogenboom et al. Antibodies that bind particular target microorganisms can (1991) Nucleic Acids Res. 19: 4133-4137). be made using any methods readily available to one skilled in Since the antibody fragments on the Surface of the phage or the art. For example, as described in U.S. Pat. No. 6,231,857 yeast are functional, phage bearing antigen binding antibody (incorporated herein by reference) three monoclonal antibod fragments can be separated from non-binding phage by anti ies, i.e., SWLA1, SWLA2, and SWLA3 have been made gen affinity chromatography (McCafferty et al. (1990) against S. mutans. Monoclonal antibodies obtained from non Nature, 348: 552-554). Depending on the affinity of the anti human animals to be used in a targeting moiety can also be body fragment, enrichment factors of 20 fold-1,000,000 fold humanized by any means available in the art to decrease their are obtained for a single round of affinity selection. immunogenicity and increase their ability to elicit anti-mi 25 Human antibodies can be produced without prior immuni crobial immune response of a human. Illustrative microor Zation by displaying very large and diverse V-gene repertoires ganisms and/or targets to which antibodies may be directed on phage (Marks et al. (1991).J. Mol. Biol. 222:581-597. are shown, for example, in Tables 5. In certain embodiments, nanobodies can be used as target Various forms of antibody include, without limitation, ing moieties. Methods of making VH (nanobodies) are also whole antibodies, antibody fragments (e.g., (Fab'), Fab'. 30 well known to those of skill in the art. The Camelidae heavy etc.), single chain antibodies (e.g., ScPV), minibodies, Di chain antibodies are found as homodimers of a single heavy miniantibody, Tetra-miniantibody, (scFv), Diabody, scDia chain, dimerized via their constant regions. The variable body, Triabody, Tetrabody, Tandem diabody, VHH, nanobod domains of these camelidae heavy chain antibodies are ies, affibodies, unibodies, and the like. referred to as V. domains or V, and can be either used per Methods of making such antibodies are well known to 35 se as nanobodies and/or as a starting point for obtaining those of skill in the art. In various embodiments, such meth nanobodies. Isolated V retain the ability to bind antigen ods typically involve providing the microorganism, or a com with high specificity (see, e.g., Hamers-Casterman et al. ponent thereof for use as an antigen to raise an immune (1993) Nature 363: 446-448). In certain embodiments such response in an organism or for use in a screening protocol V. domains, or nucleotide sequences encoding them, can be (e.g., phage or yeast display). 40 derived from antibodies raised in Camelidae species, for For example, polyclonal antibodies are typically raised by example in camel, dromedary, llama, alpaca and guanaco. one or more injections (e.g. Subcutaneous or intramuscular Other species besides Camelidae (e.g. shark, pufferfish) can injections) of the target microorganism(s) or components produce functional antigen-binding heavy chain antibodies, thereof into a Suitable non-human mammal (e.g., mouse, from which (nucleotide sequences encoding) Such naturally rabbit, rat, etc.). 45 occurring V can be obtained, e.g. using the methods If desired, the immunizing microorganism or antigen described in U.S. Patent Publication US 2006/0211088. derived therefrom can be administered with or coupled to a In various embodiments, for use in therapy, human proteins carrier protein by conjugation using techniques that are well are preferred, primarily because they are not as likely to known in the art. Such commonly used carriers which are provoke an immune response when administered to a patient. chemically coupled to the peptide include keyhole limpet 50 Comparisons of camelid V with the V domains of human hemocyanin (KLH), thyroglobulin, bovine serum albumin antibodies reveals several key differences in the framework (BSA), and tetanus toxoid. The coupled peptide is then used regions of the camelid V. domain corresponding to the to immunize the animal (e.g. a mouse or a rabbit). V/V, interface of the human V. domains. Mutation of these The antibodies are then obtained from blood samples taken human residues to V resembling residues has been per from the mammal. The techniques used to develop polyclonal 55 formed to produce "camelized' human V. domains that antibodies are known in the art (see, e.g., Methods of Enzy retain antigen binding activity, yet have improved expression mology, “Production of Antisera With Small Doses of Immu and solubility. nogen: Multiple Intradermal Injections. Langone, et al. eds. Libraries of single V, domains have also been derived for (Acad. Press, 1981)). Polyclonal antibodies produced by the example from V genes amplified from genomic DNA or animals can be further purified, for example, by binding to 60 from mRNA from the spleens of immunized mice and and elution from a matrix to which the peptide to which the expressed in E. coli (Ward et al. (1989) Nature 341: 544-546) antibodies were raised is bound. Those of skill in the art will and similar approaches can be performed using the V know of various techniques common in the immunology arts domains and/or the V, domains described herein. The iso for purification and/or concentration of polyclonal antibod lated single VH domains are called “dAbs' or domain anti ies, as well as monoclonal antibodies see, for example, Coli 65 bodies. A “dAb’ is an antibody single variable domain (V or gan, et al. (1991) Unit 9, Current Protocols in Immunology, V.) polypeptide that specifically binds antigen. A “dAb” Wiley Interscience). binds antigen independently of other V domains; however, as US 8,389,679 B2 67 68 the term is used herein, a “dAb’ can be present in a homo- or TABLE 5 heteromultimer with other V or V, domains where the other domains are not required for antigenbinding by the dAb, i.e., Illustrative antibodies that bind target microorganisms. where the dAb binds antigen independently of the additional 5 Source Antibody V or V, domains. 7,195,763 Polyclonal/monoclonal binds specific Gram (+) As described in U.S. Patent Publication US 2006/0211088 cell wall repeats methods are known for the cloning and direct Screening of 6,939,543 Antibodies against G(+) LTA 7,169,903 Antibodies against G(+) peptidoglycan immunoglobulin sequences (including but not limited to mul 6,231,857 Antibody against S. militans (Shi) tivalent polypeptides comprising: two or more variable 10 5,484,591 Gram(-) binding antibodies domains—or antigenbinding domains—and in particular V. US 2007/0231321 Diabody binding to Streptococcus Surface antigen III domains or V. domains; fragments of V, V, or V. US 2003/0124635 Antibody against S. mutans domains, such as CDR regions, for example CDR3 regions; US 2006/0127372 Antibodies to Actinomyces naeslundii, antigen-binding fragments of conventional 4-chain antibod Lactobacilitis casei ies such as Fab fragments and scFv's, heavy chain antibodies 15 US 2003/0092086 Antibody to S. sobrinus and domain antibodies; and in particular of V. sequences, and more in particular of V. sequences) that can be used as In addition, antibodies (targeting moieties) that bind other part of and/or to construct such nanobodies. microorganisms can readily be produced using, for example, the methods described above. Methods and procedures for the production of VHH/nano 20 Porphyrins. bodies can also be found for example in WO94/04678, WO In certain embodiments porphyrins, or other photosensi 96/34103, WO 97/49805, WO 97/498.05 WO 94/25591, WO tizing agents, can be used as targeting moieties in the con 00/43507 WO 01/901.90, WO 03/025020, WO 04/062551, structs described herein. In particular, metalloporphyrins, WO 04/041863, WO 04/041865, WO 04/041862, WO particularly a number of non-iron metalloporphyrins mimic 04/041867, PCT/BE2004/000159, Hamers-Casterman et al. 25 heme in their molecular structure and are actively accumu (1993) Nature 363: 446: Riechmann and Muyldermans lated by bacteria via high affinity heme-uptake systems. The (1999).J. Immunological Meth., 231: 25-38; Vu et al. (1997) same uptake systems can be used to deliver antibiotic-por Molecular Immunology, 34(16-17): 1121-1131; Nguyenetal. phyrin and antibacterial-porphyrin conjugates. Illustrative (2000) EMBO.J., 19(5): 921-930; Arbabi Ghahroudi et al. targeting porphyrins Suitable for this purpose are described in (19997) FEBS Letters 414: 521-526; van der Linden et al. 30 U.S. Pat. No. 6,066,628 and shown herein, for example, in (2000).J. Immunological Meth., 240: 185-195; Muyldermans FIGS. 1 and 2. (2001) Rev. Molecular Biotechnology 74: 277-302: Nguyen For example, certain artificial (non-iron) metalloporphy etal. (2001) Adv. Immunol. 79: 261, and the like, which are all rins (MPs) (Ga-IX, Mn-IX.) are active against Gram-negative incorporated herein by reference. and Gram-positive bacteria and acid-fast bacilli (e.g., Y. 35 enterocolitica, N. meningitides, S. marcescens, E. coli, P In certain embodiments the antibody targeting moiety is a mirabills, K. pneumoniae, K. Oxytoca, Ps. aeruginosa, C. unibody. Unibodies provide an antibody technology that pro freundii, E. aerogenes, F menigo septicum, S. aureus, B. sub duces a stable, Smaller antibody format with an anticipated tilis, S. pyogenes A, E. faecalis, M. Smegmatis, M. bovis, M. longer therapeutic window than certain Small antibody for tuber, S. cerevisiae) as described in Tables 1-5 of U.S. Pat. mats. In certain embodiments unibodies are produced from 40 No. 6,066,628. These MPs can be used as targeting moieties IgG4 antibodies by eliminating the hinge region of the anti against these microorganisms. body. Unlike the full size IgG4 antibody, the half molecule Similarly, some MPs are also growth-inhibitory against fragment is very stable and is termed a uniBody. Halving the yeasts, indicating their usefulness targeting moieties to target IgG4 molecule left only one area on the UniBody that can Candida species (e.g., Candida albicans, C. krusei, C. pillo bind to a target. Methods of producing unibodies are 45 sus, C. glabrata, etc.) and other mycoses including but not described in detail in PCT Publication WO2007/059782, limited to those caused by as Trichophyton, Epidermophyton, which is incorporated herein by reference in its entirety (see, Histoplasma, Aspergillus, Cryptococcus, and the like. also, Kolfschoten et al. (2007) Science 317: 1554-1557). Porphyrins, and other photosensitizers, also have antimi Affibody molecules are class of affinity proteins based on a crobial activity. Accordingly, in certain embodiments, the 58-amino acid residue protein domain, derived from one of 50 porphyrins, or other photosensitizers, can be used as effectors the IgG-binding domains of Staphylococcal protein A. This (e.g., attached to targeting peptides as described herein). In three helix bundle domain has been used as a scaffold for the various embodiments the porphyrins or other photosensitiz construction of combinatorial phagemid libraries, from ers can provide a dual functionality, e.g., as a targeting moiety which Affibody variants that target the desired molecules can and an antimicrobial and can be attached to a targeting pep be selected using phage display technology (see, e.g., Nordet 55 tide and/or to an antimicrobial peptide as described herein. al. (1997) Nat. Biotechnol. 15: 772-777: Ronmark et al. Illustrative porphyrins and other photosensitizers are (2002) Eur: J. Biochem., 269: 2647-2655). Details of Affibod shown in FIGS. 1-11 and described in more detail in the ies and methods of production are knownto those of skill (see, discussion of effectors below. e.g., U.S. Pat. No. 5,831,012 which is incorporated herein by Pheromones. reference in its entirety). 60 In certain embodiments, pheromones from microorgan isms can be used as targeting moieties. Illustrative phero It will also be recognized that antibodies can be prepared mones from bacteria and fungi are shown in Table 6. In certain by any of a number of commercial services (e.g., Berkeley embodiments, chimeric moieties are contemplated compris antibody laboratories, Bethyl Laboratories, Anawa, Euro ing a targeting moiety comprising or consisting of the amino genetec, etc.). 65 acid sequence (or retro or retro-inverso or beta) sequence of a Illustrative antibodies that bind various microorganisms peptide shown in Table 6 attached to one or more of the are shown in Table 5. peptides shown in Table 2. US 8,389,679 B2 69 70 TABLE 6 Illustrative bacterial and fundal pheromones utilizable as targetinc moieties.

Bacterial Pheromones Locus tag Product Sequence SEQ ID gi iPD1 Enterococcus MKOOKKHIAALLF 45.5 faecallis ALILTLWS gi 113947 Igb|AAB35253.1 iAM373 sex pheromone SIFTLWA 456 inhibito Enterococcus faecallis, Peptide, 7 aa gi Sex pheromone CAD1 LFSLWLAG 457 gi 16406|sp|P11932.1|CIA ENTFA Sex pheromone cAM373 AIFILAS 458 (Clumping-inducing agent) (CIA) gi Sex pheromone cPD1 FLWMFLSG 459 gi 2056953 Igb|AAG48144.1|AF322594 1 putative peptide DSIRDWSPTFNKIRR 460 pheromone ProA WFDGLFK Lactobacilius paracasei gi Sex pheromone inhibitor MSKRAMKKIIPLIT 461 determinant precursor LFWWTLVG (i.AD1) gi 263 62994 emb|CAM35812.1 precursor of pheromone KDEIYWKPS 462 peptide ComX Bacillus amyloliquefaciens FZE42 gi pheromone YSTCDFIM 463 gi 590.0442|ref|NP 345046.1 peptide pheromone BlpC GLWEDLLYNINRY 464 Streptococcus AHYIT pneumoniae TIGR4 gi 617436emb|CAA66791.1 competence pheromone DIRHRINNSIWRDIF 465 Streptococcus gordonii gi 61744 Olemb|CAA66786.1 competence pheromone DWRSNKIRLWWEN 466 Streptococcus gordonii IFFNKK gi ComX pheromone PTTRENDG 467 precursor Bacilius mojavensis gi 830.7874 Igb|AAL67731.1|AF456135 2 ComX pheromone LOIYTNGNWWPS 468 precursor Bacilius mojavensis gi 29377808 |ref INP 816936.1| sex pheromone inhibitor MSKRAMKKIIPLIT 469 determinant Enterococcus LFWWTLVG faecalis V583 gi 3342125.gb|AAC27522. 1 putative pheromone GAGKNLIYGMGYG 47 O Enterococcus faecium YLRSCNRL gi Competence-stimulating EMRLSKFFRDFILO 471 peptide type 1 precursor RKK (CSP-1) gi PcfP Enterococcus WSEIEINTKOSN 472 faecallis gi Prg T Enterococcus HISKERFEAY 473 faecallis gi 58616083|ref|YP 195761.1 UWaF Enterococcus 474 faecallis RKDHRTAR gi 58616111|ref|YP 195802.1 PcfP Enterococcus WSEIEINTKOSN faecallis gi 58616132|ref|YP 195769.1 ProgQ Enterococcus MKTTLKKLSRYIA 476 faecallis WWIAITLIFI gi 58616137|ref|YP 195772.1| Prg T Enterococcus HISKERFEAY 477 faecallis

US 8,389,679 B2 75 76 TABLE 6-continued Illustrative bacterial and fungal pheromones utilizable as targeting moieties.

Bacterial Pheromones Locus tag Product Sequence SEQ ID

lipopeptide mating SLTYAWCWWA 17 pheromone precursor Bap2(3) Schizophyllum commune

lipopeptide mating TSMAHAWCWWA 518 pheromone precursor Bap3 (2) Schizophyllum commune

lipopeptide mating GYCWWA 519 pheromone precursor Bbp2(8) Schizophyllum commune MFA1 USTMA A1 MLSIFAOTTOTSAS SPECIFIC PHEROMONE EPOOSPTAPOGRDN (MATING FACTOR A1) GSPIGYSSCWWA Ustilago maydis 521

M-factor mating MDSMANTWSSSWW 521 pheromone NTGNKPSETLNKT Schizosaccharomyces WKNYTPKWPYMCW pombe IA gi 5917793 Igb|AAD56043.1|AF184069 1 pheromone Mfa2 MFSLFETWAAAWK 522 Ustilago hordei WWSAAEPEHAPTNE GKGEPAPYCIIA gi Phb3. 2.42 Coprinus LTWFCWIA 523 cinereus gi putative pheromone LREKRRRRWFEAF 524 receptor STE3. 4 MGFGL Coprinelius disseminatus gi 71012805|ref|XP 758529.1 A1 - specific pheromone MLSIFAOTTOTSAS 525 Ustilago maydis 521 EPOOSPTAPOGRDN GSPIGYSSCWWA gi 72414834 emb|CAI59748.1 mating factor a1.3 MDALTLFAPWSLG 526 Sporis orium reilianum AVATEOAPWDEER PNROTFPWIGCVVA gi 7241.4854 emb|CAI59758.1 mating factor a2.1 MFIFESVVASVOAV 27 Sporis orium reilianum SWAEODOTPVSEG RGKPAVYCTIA gi rba1 gene product PWMSLLFSFLALLA 528 LILPKLSKDDPLGL TROPR gi 151941959|gb|EDN60315.1 pheromone-regulated ASISLIMEGSANIEA 529 membrane protein WGKLWWLAAALPL Saccharomyces cerevisiae AFI YJM789) gi3025.095 sp|Q07549.11SNA4 YEAST Protein SNA4 ARNVYPSVETPLLO 53 O GAAPHDNKQSLVE SPPPYVP gil 7392.1293 sp|Q08245.3|ZEO1 YEAST RecName: Full = Protein FLKKLNRKIASIFN 531 ZEO1; AltName: Full = Zeocin resistance protein 1

RecName: Full Protein DSISROGSISSGPPP 532 IGO2 RSPNK US 8,389,679 B2 77 78 Effectors. the fluorochrome with the appropriate wavelength of light Any of a wide number of effectors can be coupled to and detecting the resulting fluorescence, e.g., by microscopy, targeting moieties as described herein to preferentially visual inspection, via photographic film, by the use of elec deliver the effector to a target organism and/or tissue. Illus tronic detectors such as charge coupled devices (CCDS) or trative effectors include, but are not limited to detectable photomultipliers and the like. Similarly, enzymatic labels labels, Small molecule antibiotics, antimicrobial peptides, may be detected by providing appropriate Substrates for the porphyrins or other photosensitizers, epitope tags/antibodies enzyme and detecting the resulting reaction product. Finally, for use in a pretargeting protocol, microparticles and/or simple colorimetric labels may be detected simply by observ microcapsules, nanoparticles and/or nanocapsules, "carrier' ing the color associated with the label. vehicles including, but not limited to lipids, liposomes, den 10 Antibiotics. drimers, cholic acid-based peptide mimics or other peptide In certain embodiments chimeric moieties are provided mimics, Steroid antibiotics, and the like. comprising a targeting moiety (e.g. as described in Table 2) Detectable Labels. attached directly or through a linker to a small molecule In certain embodiments chimeric moieties are provided antibiotic and/or to a carrier (e.g., a lipid or liposome, a comprising a targeting moiety (e.g. as described in Table 2) 15 polymer, etc.) comprising a small molecule antibiotic (e.g., attached directly or through a linker to a detectable label. an antibiotics shown in Table 7). Such chimeric moieties are effective for detecting the pres ence and/or quantity, and/or location of the microorganism(s) TABLE 7 to which the targeting moiety is directed. Similarly these chimeric moieties are useful to identify cells and/or tissues Illustrative antibiotics for use in the and/or foodstuffs and/or other compositions that are infected chimeric moieties described herein. with the targeted microorganism(s). Class Generic Name Brand Name Detectable labels suitable for use in such chimeric moieties Aminoglycosides Amikacin Amikin include any composition detectable by spectroscopic, photo Gentamicin Garamycin chemical, biochemical, immunochemical, electrical, optical, 25 Kanamycin Kantrex or chemical means. Illustrative useful labels include, but are Neomycin Netilmicin Netromycin not limited to, biotin for staining with labeled streptavidin Streptomycin conjugates, avidin or streptavidin for labeling with biotin Tobramycin Nebcin conjugates fluorescent dyes (e.g., fluorescein, texas red, Paromomycin Humatin rhodamine, green fluorescent protein, and the like, see, e.g., 30 Carbacephem Loracarbef Lorabid Carbapenems Ertapenem Invanz Molecular Probes, Eugene, Oreg., USA), radiolabels Doripenem Finibax (e.g., *H, 125I, 35S, 14C, 32p 99Tc, 208Pb, 7Ga, Ga, 7°As, Imipenem Cilastatin Primaxin In 113In 97Ru,62Cu, 641Cu, 52Fe, 52"Mn, 5 Cr, 186Re, Meropenem Merrem 188Re, 77As, 90Y. 7Cu, 169Er 12'Sn, 127Te, 142Pr 14.Pr Cephalosporins Cefadroxi Duricef 35 (First Cefazolin Ancef 198Au, 199 Au, 161Tb, 109Pd, 165Dy, 149Pm, 15Pm, 15Sm, generation) Cefalotin or Cefalothin Keflin 157Gd, 15°Gd, 166Ho, 72Tm, 169Yb, 77Lu, 103Rh, '''Ag, and Cefalexin Keflex the like), enzymes (e.g., horse radish peroxidase, alkaline Cephalosporins Cefaclor Ceclor phosphatase and others commonly used in an ELISA), Vari (Second Cefamandole Mandole generation) Cefoxitin Mefoxin ous colorimetric labels, magnetic or paramagnetic labels Cefprozil Cefail (e.g., magnetic and/or paramagnetic nanoparticles), spin 40 Cefuroxime Ceftin, Zinnat labels, radio-opaque labels, and the like. Patents teaching the Cephalosporins Cefixime Suprax use of such labels include, for example, U.S. Pat. Nos. 3,817, (Third Cefinir Omnicef generation) Cefitoren Spectracef 837; 3,850,752; 3,939,350; 3,996.345; 4,277,437; 4,275,149: CefoperaZone Cefobid and 4,366,241. Cefotaxime Claforan It will be recognized that fluorescent labels are not to be 45 Cefpodoxime limited to single species organic molecules, but include inor Ceftazidime Fortaz Ceftibuten Cedax ganic molecules, multi-molecular mixtures of organic and/or Ceftizoxime inorganic molecules, crystals, heteropolymers, and the like. Ceftriaxone Rocephin Thus, for example, CdSe CdS core-shell nanocrystals Cephalosporins Cefepime Maxipime enclosed in a silica shell can be easily derivatized for coupling 50 (Fourth generation) to a biological molecule (Bruchez et al. (1998) Science, 281: Cephalosporins Ceftobiprole 2013-2016). Similarly, highly fluorescent quantum dots (Zinc (Fifth Sulfide-capped cadmium selenide) have been covalently generation) coupled to biomolecules for use in ultrasensitive biological Glycopeptides Teicoplanin 55 Vancomycin Vancocin detection (Warren and Nie (1998) Science, 281: 2016-2018). Macrollides Azithromycin Zithromax In various embodiments spin labels are provided by Clarithromycin Biaxin reporter molecules with an unpaired electron spin which can Dirithromycin be detected by electron spin resonance (ESR) spectroscopy. Erythromycin Erythocin, Erythroped Illustrative spin labels include organic free radicals, transi Roxithromycin tional metal complexes, particularly Vanadium, copper, iron, 60 Troleandomycin and manganese, and the like. Exemplary spin labels include, Telithromycin Ketek for example, nitroxide free radicals. Monobactams Aztreonam Penicillins Amoxicillin Novamox, Amoxil Means of detecting such labels are well known to those of Ampicillin skill in the art. Thus, for example, where the label is a radio Azlocillin active label, means for detection include a Scintillation 65 Carbenicillin counter or photographic film as in autoradiography. Where Cloxacillin the label is a fluorescent label, it may be detected by exciting US 8,389,679 B2 79 80 TABLE 7-continued visible, ultraviolet, infrared, etc.) in order to give a phototoxic response in the target organism(s), often via oxidative dam Illustrative antibiotics for use in the age. chimeric moieties described herein. Currently, the major use of PACT is in the disinfection of Class Generic Name Brand Name blood products, particularly for viral inactivation, although more clinically-based protocols are used, e.g. in the treatment Dicloxacillin Flucloxacillin Floxapen of oral infection or topical infection. The technique has been Mezlocillin shown to be effective in vitro against bacteria (including Meticillin drug-resistant strains), yeasts, viruses, parasites, and the like. Nafcillin 10 Attaching a targeting moiety (e.g., a targeting peptide as Oxacillin Penicillin shown in Table 2) to the photosensitizer, e.g., as described Piperacillin herein, provides a means of specifically or preferentially tar Ticarcillin geting the photosensitizer(s) to particular species or strains(s) Polypeptides Bacitracin of microorganism. Colistin Polymyxin B 15 A wide range of photosensitizers, both natural and Syn Quinolones Mafenide thetic are known to those of skill in the art (see, e.g., Wain Prontosil (archaic) wright (1998).J. Antimicrob. Chemotherap. 42: 13-28). Pho Sulfacetamide tosensitizers are available with differing physicochemical Sulfamethizole make-up and light-absorption properties. In various embodi Sulfanilimide (archaic) SulfaSalazine ments photosensitizers are usually aromatic molecules that Sulfisoxazole are efficient in the formation of long-lived triplet excited Trimethoprim Trimethoprim Bactrim states. In terms of the energy absorbed by the aromatic-sys Sulfamethoxazole (Cotrimoxazole) (TMP-SMX) tem, this again depends on the molecular structure involved. Tetracyclines Demeclocycline For example: furocoumarin photosensitizers (psoralens) Doxycycline Vibramycin 25 absorb relatively high energy ultraviolet (UV) light (c. 300 Minocycline Minocin 350 nm), whereas macrocyclic, heteroaromatic molecules Oxytetracycline Terracin Tetracycline Sumycin Such as the phthalocyanines absorb lower energy, near-infra Cationic steroid squalamine red light. antibiotics CSA-8 Illustrative photosensitizers include, but are not limited to CSA-11 30 porphyrinic macrocyles (especially porphyrins, chlorines, CSA-13 CSA-15 etc., see, e.g., FIGS. 1 and 2). In particular, metalloporphy CSA-25 rins, particularly a number of non-iron metalloporphyrins CSA-46 mimic heme in their molecular structure and are actively CSA-54 accumulated by bacteria via high affinity heme-uptake sys CSA-90 35 CSA-97 tems. The same uptake systems can be used to deliver antibi Others Arsphenamine Salvarsan otic-porphyrin and antibacterial-porphyrin conjugates. Illus Chloramphenicol Chloromycetin trative targeting porphyrins Suitable for this purpose are Clindamycin Cleocin described in U.S. Pat. No. 6,066,628 and shown herein in Lincomycin FIGS. 1 and 2. Ethambutol Fosfomycin 40 For example, certain artificial (non-iron) metalloporphy Fusicic acid Fucidin rins (MPs) (Ga-IX, Mn-IX.) are active against Gram-negative Furazolidone and Gram-positive bacteria and acid-fast bacilli (e.g., Y. Isoniazid Linezolid Zyvox enterocolitica, N. meningitides, S. marcescens, E. coli, P Metronidazole Flagyl mirabilis, K. pneumoniae, K. Oxytoca, Ps. aeruginosa, C. Mupirocin Bactroban 45 freundii, E. aerogenes, F menigo septicum, S. aureus, B. sub Nitrofurantoin Macrodantin, tilis, S. pyogenes A, E. faecalis, M. Smegmatis, M. bovis, M. Macrobid Platensinycin tuber, S. cerevisiae) as described in Tables 1-5 of U.S. Pat. Pyrazinamide No. 6,066,628. These MPs can be used as targeting moieties Quinupristin/Dalfopristin Syncercid against these microorganisms. Rifampin or Rifampicin 50 Similarly, some MPs are also growth-inhibitory against Tinidazole yeasts, indicating their usefulness targeting moieties to target Candida species (e.g., Candida albicans, C. krusei, C. pillo sus, C. glabrata, etc.) and other mycoses including but not Porphyrins and Non-Porphyrin Photosensitizers. limited to those caused by as Trichophyton, Epidermophyton, In certain embodiments, porphyrins and other photosensi 55 Histoplasma, Aspergillus, Cryptococcus, and the like. tizers can be used as targeting moieties and/or as effectors in Other photosensitizers include, but are not limited to cya the methods and compositions of this invention. A photosen nines (see, e.g., FIG. 6) and phthalocyanines (see, e.g., FIG. sitizer is a drug or other chemical that increases photosensi 4), azines (see, e.g., FIG. 5) including especially methylene tivity of the organism (e.g., bacterium, yeast, fungus, etc.). As blue and toluidine blue, hypericin (see, e.g., FIG. 8), acridines targeting moieties the photosensitizers (e.g., porphyrins) are 60 (see, e.g., FIG.9) including especially Rose Bengal (see, e.g., preferentially uptaken by the target microorganisms and FIG. 10), crown ethers (see, e.g., FIG. 11), and the like. In certain embodiments the photosensitizers are toxic or thereby facilitate delivery of the chimeric moiety to the target growth inhibitors without light activation. For example, some microorganism. non-iron metalloporphyrins (MPs) (see, e.g., FIGS. 1 and 2 As effectors, photosensitizers can be useful in photody 65 herein) possess a powerful light-independent antimicrobial namic antimicrobial chemotherapy (PACT). In various activity. In addition, haemin, the most well known natural embodiments PACT utilizes photosensitizers and light (e.g., porphyrin, possesses a significant antibacterial activity that US 8,389,679 B2 81 82 can augmented by the presence of physiological concentra Frequently the secondary structures of these molecules tions of hydrogen peroxide or a reducing agent. follow 4 themes, including i) C.-helical. ii) B-stranded due to Typically, when activated by light, the toxicity or growth the presence of 2 or more disulfide bonds, iii) B-hairpin or inhibition effect is substantially increased. Typically, they loop due to the presence of a single disulfide bond and/or generate radical species that affect anything within proximity. cyclization of the peptide chain, and iv) extended. Many of In certain embodiments to get the best selectivity from tar these peptides are unstructured in free solution, and fold into geted photosensitizers, anti-oxidants can be used to quench their final configuration upon partitioning into biological un-bound photosensitizers, limiting the damage only to cells membranes. The ability to associate with membranes is a where the conjugates have accumulated due to the targeting definitive feature of antimicrobial peptides although mem peptide. The membrane structures of the target cell act as the 10 brane permeabilisation is not necessary. These peptides have proton donors in this case. In typical photodynamic antimicrobial chemotherapy a variety of antimicrobial activities ranging from membrane (PACT) the targeted photosensitizer is “activated by the appli permeabilization to action on a range of cytoplasmic targets. cation of a light source (e.g., a visible light source, an ultra The modes of action by which antimicrobial peptides kill violet light source, an infrared light source, etc.). PACT appli 15 bacteria is varied and includes, but is not limited to disrupting cations however need not be limited to topical use. Regions of membranes, interfering with metabolism, and targeting cyto the mouth, throat, nose, sinuses are readily illuminated. Simi plasmic components. In many cases the exact mechanism of larly regions of the gut can readily be illuminated using endo killing is not known. scopic techniques. Other internal regions can be illumined In various embodiments one or more antimicrobial pep using laparoscopic methods or during other Surgical proce tides are used alone (e.g., as broad spectrum antimicrobials) dures. For example, in certain embodiments involving the and/or are provided as effectors attached to one or more insertion or repair or replacement of an implantable device targeting moieties thereby providing a narrower spectrum (e.g., a prosthetic device) it contemplated that the device can (directed) antimicrobial. In certain embodiments one or more be coated or otherwise contacted with a chimeric moiety antimicrobial peptides are provided as effectors attached to comprising a targeting moiety attached to a photosensitizer as 25 one or more targeting moieties and/or one or more effectors described herein. During the Surgical procedure and/or just thereby providing a component of a multiple effector com before closing, the device can be illuminated with an appro position/strategy. priate light Source to activate the photosensitizer. Suitable antimicrobial peptides for this use include, but are The targeted photosensitizers and uses thereof described not limited to the antimicrobial peptides found in Table 2, herein are illustrative and not to be limiting. Using the teach 30 and/or Table 9, and/or Table 10. ings provided herein, other targeted photosensitizers and uses thereof will be available to one of skill in the art. TABLE 8 Antimicrobial Peptides. Novel antimicrobial peptides. In certain embodiments the chimeric moieties described herein include one or more antimicrobial peptides (e.g., cer 35 ID Structure/sequence SEQ ID NO tain peptides shown in Table 2 and/or Table 10) as effectors. Thus, for example, in certain embodiments, where the pep K-1 GLGRVIGRLIKQIIWRR 533 tides described in Table 2 are exploited for their targeting K-2 WYRKRKSILKIYAKLKGWH 534 ability, chimeric moieties are contemplated comprising one or more of the targeting peptides of Table 2 attached to one or 40 K-3 AFYORKENVISLDPREWLGFNVTEK 535 more of the antimicrobial peptides of Table 10. In certain K-4 DKKRWIERIKSFSLRDEWIHFGELCIYWGK 536 embodiments chimeric moieties are contemplated compris ing one or more of the targeting peptides of Table 2 attached K-5 RSSYNGFSKICFLKIEHFGSYSYOGR s37 to one or more of the antimicrobial peptides of Table 2. In K-6 WLNAISLYGRIG 538 certain embodiments chimeric moieties are contemplated 45 comprising other targeting moieties (e.g., porphyrins, anti K-7 NYRLWNAIFSKIFKKKFIKF 539 bodies, etc.) attached to one or more of the antimicrobial peptides of Table 2. K-8 KIL. K. FLF K. KWF 54 O Antimicrobial peptides (also called host defense peptides) K-9 FI RK FLK KW LL 541 are an evolutionarily conserved component of the innate 50 immune response and are found among all classes of life. K-10 KLFKFLRKHLL 542 Unmodified, these peptides are potent, broad spectrum anti biotics which demonstrate potential as novel therapeutic K- 11 KIL K FLF K OVF 543 agents. Antimicrobial peptides have been demonstrated to kill K-12 KIL. K. KLF K FWF 544 Gram-negative and Gram-positive bacteria (including strains 55 that are resistant to conventional antibiotics), mycobacteria K-13 GIL. K. KLF. T. KWF 5.45 (including Mycobacterium tuberculosis), enveloped viruses, K-14 R K FL H K LF 546 and fungi. Naturally-occurring antimicrobial peptides are typically K-15 R. KNL R. WLF 47 short peptides, generally between 12 and 50 amino acids. 60 These peptides often include two or more positively charged K-16 FI RK FLQ KLHL 548 residues provided by arginine, lysine or, in acidic environ K-17 FTRKELKFLHL 549 ments, histidine, and frequently a large proportion (generally >50%) of hydrophobic residues (see, e.g., Papagianni et al. K-18 KKFKKFKWLKIL 550 (2003) Biotechnol Adv 21: 465: Sitaram and Nagaraj (2002) 65 K-19 LKLIKLKKLKF 551 Curr Pharm Des 8: 727; Dürret al. (2006) Biochim. Biophys. Acta 1758: 1408-1425). US 8,389,679 B2 83 84 In certain embodiments peptides that induce alterations in TABLE 9- continued phenotype or other biological activities can also be used as antimicrobial effector moieties. Illustrative alternative pep Novel growth phenotype-inducing or peptides with tides are shown in Table 9. other activities. SEQ TABLE 9 ID ID Organism, effect Structure/sequence NO Novel growth phenotype-inducing or peptides with other activities. G-5. M. xanthus : RDMTWAGKRPNFLIITTDEE 556 Altered cell SEQ 10 morphology ID ID Organism, effect Structure/sequence NO G- 6 M. Xanthus: NTSIWCAWTFAPIKEWPLLWRAGLT 557 Altered cell LRSROS G-1 S. multans: Ca2+ DSSOSDSDSDSNSSNTNSNSSITNG 552 morphology binding 15 G-7 M. xanthus : OAKVEREVERDLWYTLRRLCDPSG 558 G-2 S. mutans: biofilm LPGTLHIQAEFPWOLEAGSLIQIFD 553 Altered cell SERTK Structure morphology

G-3 S. mutans: biofilm LACTTPWGAWLYLGAEWCAGAAWI 554 G-8 S. mutans : PRMIDIISFHGCHGDHOVWTDPOAT 559 Structure YYGAN Altered biofilm ALPR Structure G-4 S. multans : EIPIOLANDLANYYDISLDSIFFW 555 Biofilm structure Other illustrative antimicrobial peptides include, but are not limited to the AMPs of Table 10.

TABL E 1O Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main.

SEO ID Effector Structure/Sequence APOO274 1BH4, Circulin A GIPCGESCWWIPCISAALGCSCKNKWC 560 (CirA, plant YRN cyclotides, XXC, ZZHp)

APOOO36 1BNB. Beta- defensin. 1 DFASCHTNGGICLPNRCPGHMIOIGICF 561 (cow) RPRWKCCRSW

APOOO47 1BNB, Bovine GPLSCGRNGGVCIPIRCPVPMROIGTC 562 neutrophill beta- defensin 12 (BNBD-12, cow)

APOO 428 1CO1, MiAMP1 SAFTWWSGPGCNNRAERYSKCGCSAI 563 (Macadamia integrifolia HOKGGYDFSYTGOTAALYNOAGCSG antimicrobial peptide 1, VAHTRFGSSARACNPFGWKSIFIOC plant)

APOO154 1CIX, Tachy statin A2 YSRCOLOGFNCVVRSYGLPTIPCCRGL 564 (Horseshoe crabs, TCRSYFPGSTYGRCORY Crustacea, BBS)

APOO145 1CW5, WNYGNGVSCSKTKCSVNWGOAFOER 565 Carnobacteriocin B2 YTAGINSFWSGWASGAGSIGRRP (CnbB2, class IIA bacteriocin, bacteria)

APOO153 1CZ6, Androctonin RSVCROIKICRRRGGCYYKCTNRPY 566 (scorpions)

APOO152 1D6X, Tritrpticin WRRFPWWWPFLRR 567 (synthetic)

APOO2O1 1D7N, Mastoparan INLKALIAALAKKIL 568 (insect)

APOO14 O 1D9 J, CecropinA 569 Magainin2 hybrid (synthetic)

APOO178 1DFN, human alpha DCYCRIPACIAGERRYGTCIYOGRLW st O Defensin HNP-3 AFCC (human neutrophil peptide-3, HNP3, human defensin, ZZHh) US 8,389,679 B2 85 86 TABL E 1 O - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APO1153 DQC, Tachycitin YLA FRCGRYSPCLDDGPNWNLYSCCS sf1 (horseshoe crabs, FYNCHKCLARLENCPKGLHYNAYLK Crustacea, BBS) WCDWPSKAGCT

APOO 437 DUM, Magainin 2 GIG KYLHSAKKFGKAWWGEIMNS analog (synthetic)

APOO 451 E4S, Human beta DHYNCVSSGGOCLYSACPIFTKIOGTC defensin. 1 (HBD-1, KAKCCK human defensin)

APOO149 EWS, Rabbit kidney MPCSCKKYCDPWEWIDGSCGLFNSKY defensin. 1 (RK-1) ICC REK

APOO141 FOE, CecropinA KWK KKIPKFLHSAKKF sts Magainin2 Hybrid (P18, synthetic)

APOO142 FOG, CecropinA KLK KKIGIGKFLHSAKKF 576 Magainin2 Hybrid (synthetic)

APOO143 FOH, CecropinA KKIGIGKFLHSAKKF 577 Magainin2 Hybrid (synthetic)

APOO524 FD4, Human beta GIG DPWTCLKSGAICHPVFCPRRYKOI defensin 2 (HBD-2, human defensin, ZZHh)

APOO438 FJN, Mussel Defensin GFGCPNNYOCHRHCKSIPGRCGGYCG st 9 MGD-1 GWHRLPCTCYRCG

APOO155 FRY, SMAP-29 RGLRRLGRKIAHGWKKYGPTWLRIIRI 58 O (SMAP29, sheep AG cathelicidin)

APOO15 O G89, Indolicidin (cow 581 cathelicidin, BBN, ZZHa)

APOO156 GR4, Microcin J25. WGIGTPISFYGGGAGHWPEYF 582 inear (MccJ25, bacteriocin, bacteria)

APOO151 HR1, Indolicidin P to ILAWKWAWWAWRR 583 A mutant (synthetic)

APOO1.96 HU5, Ovispirin-1 KNLRRIIRKIIHIIKKYG 584 (synthetic)

APOO1.97 HU6, Novispirin G10 KNLRRIIRKGIHIIKKYG 585 (synthetic)

APOO198 HU7, Novispirin T7 KNLRRITRKIIHIIKKYG 586 (synthetic)

APOO445 HVZ, Monkey RTD-1 GFCRCLCRRGVCRCICTR 587 (rhesus theta-defensin-1, minidefensin-1, animal

APOO 103 i2v, Heliomicin variant IGSCWWGAWNYTSDCNGECLLRG 588 (Hel-LL, synthetic) YKGGHCGSFANWNCWCET

APOO216 ICA Phormia defensin ATCDLLSGTGINHSACAAHCLLRGNR 589 A (insect defensin A) GGYCNGKGWCWCRN

APO1224 Jo3, Gramicidin B WGALAWWWWLFLWLW. 590 (bacteria)

APO1225 jo4, Gramicidin C WGALAWWWWLYLWLW. 591 (bacteria) US 8,389,679 B2 87 88 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOO191 1KFP, Gomesin (Gm, ECRRLCYKORCVTYCRGR 592 Spider, XXA)

APOO283 1KJ6, Huamn beta GIINTLOKYYCRVRGGRCAVLSCLPKE 593 defensin 3 (HBD-3 EOIGKCSTRGRKCCRRKK human defensin, ZZHh)

APOO 147 1KV4, Moricin (insect, AKIPIKAIKTWGKAWGKGLRAINIASTA 594 silk moth) NDWFNFLKPKKRKA

APOO227 1L4V, Sapecin (insect, ATCDLLSGTGINHSACAAHCLLRGNR 595 flesh fly) GGYCNGKAWCWCRN

APO1161. 1L.9L. Human GRDYRTCLTIVOKLKKMVDKPTORSV 596 granulysin (hugiran) SNAATRWCTRGRSRWRDWCRNFMRR YQSRVIQGLVAGETAQQICEDLRLCIP STGPL

APOOO26 LFC, Lactoferricin B FKCRRWOWRMKKLGAPSITCVRRAF 597 (Lfcine, cow, ZZHa)

APOO193 M4F, human LEAP-1 DTHFPICIFCCGCCHRSKCGMCCKT 598 (Hepcidin 25)

APOO499 MAG Gramicidin. A WGALAWWWWLWLWLW. 5.99 (gA, bacteria)

APOO 403 MMO Termicin ACNFOSCWATCOAOHSIYFRRAF CDR (termite defensin, insect SOCKCWFVRG defensin)

APOO194 MMC, Ac-AMP2 WGECVRGRCPSGMCCSOFGYCGKGP (plant defensin, BBS) KYCGR

APO12O6 MOZ, Mersacidin CTFTLPGGGGVCTLTSECC (bacteria)

APOO 429 NKL, Porcine NK GYFCESCRKIIOKLEDMVGPOPNEDTV 603 Lysin (pig) TOAASQVCDKLKILRGLCKKIMRSFL RRISWDILTGKKPOAICVDIKICKE

APOO 633 og 7, Sakacin P/ KYYGNGWHCGKHSCTWDWGTAIGNI Sakacin 674 (SakP, GNNAAANWATGGNAGWNK class IIA bacteriocin, bacteria)

APOO195 1PG1, Protegrin 1 RGGRLCYCRRRFCWCWGR 605 (Protegrin-1, PG-1, pig cathelicidin, XXA, ZZHa, BBBm)

APOOS28 1PXQ, Subtillosin. A NKGCATCSIGAACLWDGPIPDFEIAGA 606 (XXC class I TGLFGLWG bacteriocin, Gram positive bacteria)

APOO48O 1971, Microcin J25 WGIGTPIFSYGGGAGHWPEYF (cyclic MccJ25, class I microcins, bacteriocins, Gram-negative bacteria, XXC, BBP)

APOO211 1RKK, Polyphemusin I 608 (crabs, Crustacea)

APOO43 O 1T51, ISCT (Scorpion) ILGKIWEGIKSLF 609

APOO731 1ut3, Sphenis cin-2 SFGLCRLRRGFCARGRCRFPSIPIGRCS 610 (Sphe-2, penguin RFVOCCRRVW defensin, avian defensin) US 8,389,679 B2 89 90 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

Effector Structure/Sequence

APOOO13 WM5, Aurein 1.2 GLFDIIKKIAESF (frog)

APOO214 WO1, Tachyples in I KWCFRWCYRGICYRRCR (crabs, Crustacea, XXA, ZZHa)

APOO 644 XCO, Pardaxin 4 GFFALIPKIISSPLFKTLLSAWGSALSSS (Pardaxin P-4, Pardaxin GGOE P4, Pa4, flat fish)

APOO493 XKM Distinctin (two NLVSGLIEARKYLEOLHRKLKNCKW chains for stability and transport? frog)

APOO42O XV3, Penaeidin-4d HSSGYTRPLRKPSRPIFIRPIGCDWCYGI (penaeidin 4, shrimp, PSSTARLCCFRYGDCCHL Crustacea)

APOOO35 YTR Plantaricin. A KSSAYSLOMGATAIKOWKKLFKKWGW (Plina, bacteriocin, bacteria)

APOO166 Z64, Pleurocidin (fish) GWGSFFKKAAHWGKHWGKAALTHYL

APOO78O Z6W, Human GRRRRSVOWCAVSOPEATKCFOWOR actoferricin NMRKVRGPPVSCIKRDSPIOCIOA

APOO549 ZFU, Plectasin (fungi, GFGCNGPWDEDDMOCHNHCKSIKGY fungal defensin) KGGYCAKGGFWCKCY

APOO177 ZMH, human alpha CYCRIPACIAGERRYGTCIYOGRLWAF Defensin HNP-2 CC (human neutrophil peptide-2, HNP2, human defensin, ZZHh)

APOO179 1ZMM, human alpha WCSCRLWFCRRTELRWGNCLIGGWSFT 621 Defensin HNP-4 YCCTRVD (human neutrophil peptide-4, HNP4, human defensin)

APOO18O 1ZMP, human alpha OARATCYCRTGRCATRESLSGVCEISG 622 Defensin HD-5 (HD5, RLYRLCCR human defensin)

APOO181 1ZMQ, human alpha STRATCHCRRSCYSTEYSYGTCTVM 623 Defensin HD - 6 (HD6, GINHRFCCL human defensin)

APOO399 1ZRW, Spinigerin HVDKKVADKWLLLKOLRIMRLLTRL 624 (insect, termite)

APO1157 1ZRX, Stomoxyn RGFRKHFNKLWKKWKHTISETAHWAK 625 (insect) DTAWIAGSGAAWWAAT

APOO 637 2A2B, Curvac in A/ ARSYGNGVYCNNKKCWVNRGEATOS 626 Sakacin A (CurA, Saka, IIGGMISGWASGLAGM class IIA bacteriocin, bacteria)

APOO558 2B68, Co-Def GFGCPGNOLKCNNHCKSISCRAGYCD 627 (Crassostrea gigas AATLWLRCTCTDCNGKK defensin, oyster defensin, animal defensin)

APO1154. 2B9K, LCI (bacteria) AIKLVOSPNGNFAASFWLDGTKWIFKS 628 KYYDSSKGYWWGIYEWWDRK

APO1 OO 5 2DCV, Tachystatin B1 YWSCLFRGARCRWYSGRSCCFGYYCR 629 (BBS, horseshoe crabs) RDFPGSIFGTCSRRNF US 8,389,679 B2 91 92 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main.

SEQ ID Effector Structure/Sequence

APO1 OO6 2DCW, Tachystatin B1 YITCLFRGARCRWYSGRSCCFGYYCR 63 O (BBS, horseshoe crabs) RDFPGSIFGTCSRRNF

APOO275 2ERI, Circulin B (Cir CGESCWFIPCISTLLGCSCKNKWCYRN 631 plant cyclotides, XXC, GWIP ZZHp)

APOOf Of 2f3a, LLAA (LL-37 RLFDKIROVIRKF 632 derived aurein 1.2 analog, retro-FK13, synthetic)

APOO708 2fbs FK-13 (FK13, FKRIVORIKDFLR 633 NMR-discovered LL-37 core peptide, XXA, ZZHs, synthetic)

APOOO88 2G9L, Gaegurin-4 GILDTLKOFAKGWGKDLVKGAAQGW 634 (Gaegurin 4, frog) LSTWSCKLAKTC

APO1 O11 2G9P, Latarcin 2a GLFGKLIKKFGRKAISYAWKKARGKH 635 (Litc2a, BBM, spider)

APOO 612 2GDL, Fowlicidin-2 LVORGRFGRFLRKIRRFRPKVTITIOGS 636 (chCATH-2, bird ARFG cathelicidin, chicken cathelicidin, BBL)

APOO4 O2 2GL1, WrD2 (Vigna KTCENLANTYRGPCFTTGSCDDHCKN 637 radiata defensin 2, plant KEHLRSGRCRDDFRCWCTRNC defensin, mung bean)

APOO285 2GW9, Cryptdin-4 GLLCYCRKGHCKRGERWRGTCGIRFL 638 (Crp4, animal defensin, YCCPRR alpha, mouse)

APOO 613 2hfir Fowlicidin-3 RWKRFWPLWPWAINTWAAGINLYKAI 639 (chCATH-3, bird RRK cathelicidin, chicken cathelicidin)

APO1 OOf 2JMY CM15 64 O (Synthetic)

APOO728 2ni, Arenicin-2 (marine 641 polychaeta, BBBm)

APOO 473 2jos, Piscidin 1 (fish) 642

APO1151 2.JPJ, Lactococcin G-a GTWDDIGOGIGRWAYWWGKALGNLS 643 (chain a class IIb DVNOASRINRKKKH bacteriocin, bacteria. For chain b, see info)

APOOff 2py, Phylloseptin-H2 FLSLIPHAINAVSTLWHHF 644 (PLS-H2, Phylloseptin 2, PS-2) (XXA, frog)

APOO546 2qO, Phylloseptin-1 FLSLIPHAINAWSAIAKHN 645 (Phylloseptin-H1, PLS H1, PS-1, XXA, frog)

APOO758 2q1, Phylloseptin-3 FLSLIPHAINAWSALANHG 646 (Phylloseptin-H3, PLS H3, PS-3) (XXA, frog)

APOO727 2sb, Arenicin-1 (marine 647 polychaeta, BBBm)

APOO592 2k10, Ranatuerin-2CS a GILSSFKGWAKGWAKDLAGKLLETLK 648 (frog) CKITGC

US 8,389,679 B2 95 96 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOO373 O96O59, Moric in 2 AKIPIKAIKTWGKAWGKGLRAINIASTA 670 (insect) NDWFNFLKPKKRKH

APOO449 PO1190, Melanotropin SYSMEHFRWGKPW 671 alpha (Alpha-MSH)

APOO187 PO1376, WWCACRRALCLPRERRAGFCRIRGRIH 672 CORTICOSTATIN III PLCCRR (MCP-1, rabbit neutrophill peptide 1, NP-1) (animal defensin, alpha-defensin, rabbit)

APOO188 PO1377, WWCACRRALCLPLERRAGFCRIRGRIH 673 CORTICOSTATIN IV PLCCRR (MCP-2, rabbit neutrophil defensin 2, NP-2, animal defensin, rabbit)

APOOO49 PO1505, Bombinin GIGALSAKGALKGLAKGLAEHFAN 674 (toad)

APOO139 PO1507, Cecropin. A KWKLFKKIEKVGONIRDGIIKAGPAVA 675 (insect, ZZHa) WWGOATOIAK

APOO128 PO1509, Cecropin B KWKIFKKIEKWGRNIRNGIIKAGPAWA 676 (insect, silk moth) WLGEAKAL

APOO131 PO1511, Cecropin D WNPFKELERAGORVRDAIISAGPAVA 677 (insect, moth) TVAQATALAK

APOO136 PO1518, Crabrolin FLPLILRKIWTAL 678 (insect, XXA)

APOO183 PO4142, Cecropin B RWKIFKKIEKMGRNIRDGIWKAGPAIE 6.79 (insect) WLGSAKAI

APOO448 PO42O5, Mastoparan M INIKAIAALAKKLL 68O (MP-M, insect, XXA)

APOO234 PO 6833, SDEKASPDKHHRFSLSRYAKLANRL.A. 681 Seminalplasmin (SPLN, NPKILLETFLSKWIGDRGNRSW calcium transporter inhibitor, caltrin, cow)

APOO314 PO7466, Rabbit WFCTCRGFLCGSGERASGSCTINGWRH 682 neutrophill peptide 5 TLCCRR (NP-5, animal defensin, alpha-defensin)

APOO189 PO7467, Rabbit WSCTCRRFSCGFGERASGSCTWINGWR 683 neutrophill peptide 4 HTLCCRR (NP-4)

APOO186 PO7468, GRCVCRKOLLCSYRERRIGDCKIRGV 684 CORTICOSTATIN II RFPFCCPR (Rabbit neutrophil peptide 3b (NP-3b, rabbit)

APOO185 PO7469, ICACRRRFCPNSERFSGYCRWNGARY 685 CORTICOSTATIN I WRCCSRR (rabbit)

APOO217 PO7469, Rabbit GICACRRRFCPNSERFSGYCRWNGAR 686 neutrophil defensin 3a YVRCCSRR (NP-3a, animal defensin, alpha defensin)

APOOO67 PO7493 Bombolitin II SKITDILAKLGKVLAHW 687 (insect, bee) US 8,389,679 B2 97 98 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effecto r Structure/Sequence

POOO68 PO7494, Bombolitin III IKIMDILAKLGKWLAHW 688 (insect bee)

POOO69 PO7495, Bombolitin IW INIKDILAKLWKWLGHW 689 (insect bee)

POOOf O PO7496, Bombolitin W INWLGILGLIGKALSHL 69 O. (insect bee)

POO236 PO7504, Pyrularia KSCCRNTWARNCYNWCRLPGTISREIC 691 thionin (Pp-TH, plant) AKKCDCKIISGTTCPSDYPK

POO23 O PO8375, Sarcotoxin IA GWLKKIGKKIERVGO HTRDATIOGLGI 692 (insect flesh AQQAANVAATAR

POO231 PO8376, Sarcotoxin IB GWLKKIGKKIERVGO HTRDATIOVIG 693 (insect flesh WAQQAANVAATAR

POO232 PO3377, Sarcotoxin IC GWLRKIGKKIERVGO HTRDATIOVLGI 694 (insect flesh AQQAANVAATAR

POOO66 P10521, Bombolitin I IKITTMLAKLGKWLA 695 (insect bee)

P10946, Lantibiotic WKSESLCTPGCWTGA LOTCFLOTLTC 696 subtili n (class I NCKISK bacteri ocin, bacteria)

POO312 Cryptdin-2 LRDLWCYCRARGCKG RERMINGTCRK 697 animal defensin, GHLLYMLCCR mouse)

POO2O5 P13068, Nisin. A ITSISLCTPGCKTGA MGCNMKTATC 698 antib iotic, class I HCSIHWSK bacteri ocin, bacteria)

POO215 P14214, Tachyples in II RWCFRVCYRGICYRKCR 699 (crabs, Crustacea)

POO212 P1.4216, Polyphemus in 7 OO I (cra bs Crustacea, XXA, ZZ Ha. Derivat ives: T22)

POO134 P14661, Cecropin P1 SWLSKTAKKLENSAK KRISEGIAIAIQ 7 O1 (pig) GGPR

POOO11 Bactericidin B2 WNPFKELERAGORVR DAVISAAPAWA 7 O2 TWGOAAAIARG

POOO32 P14663, Bactericidin B WNPFKELERAGORVR DAIISAGPAWA 7O3 3 (inse ct) TWGOAAAIARG

POOO33 P14664, Bactericidin B WNPFKELERAGORVR DAIISAAPAWA 704 4 (inse ct) TWGOAAAIARG

POOO34 P14665 Bactericidin B WNPFKELERAGORVR DAVISAAAWAT 7Os 5P (ins ect) WGOAAAIARG

POO125 Cecrop in RWKIFKKIEKVGONI RDGIWKAGPAW 706 silk moth) AWWGOAATI

POOOO2 P1545 O, ABAECIN YVPLPNVPOPGRRPF 707 (insect honeybee) KWPOGY

POOSOS P15516, human Histatin DSHAKRHHGYKRKFHEKHHSHRGY 7 OS 5 (ZZHS ; derivatives Dh-5)

POOS2O P15516, human Histatin 3 DSHAKRHHGYKRKFHEKHHSHRGYR SNYLYDN

POO523 P15516, human Histatin 8 KFHEKHHSHRGY US 8,389,679 B2 99 100 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main.php).

Effector Structure/Sequence

POO226 P17722, Royalisin WTCDLLSFKGOVNDSACAANCLSLGK (insect, honeybee) AGGHCEKWGCICRKTSFKDLWDKRF

POO213 P18252, Tachyplesin III KWCFRWCYRGICYRKCR (horseshoe crabs, Crustacea)

POO233 P18312, Sarcotoxin ID GWIRDFGKRIERVGOHTRDATIOTIAV (insect, flesh AQQAANWAATLKG

P19578, Lantibiotic TAGPAIRASWKOCOKTLKATRLFTVS PEP5 (class I CKGKNGCK bacteriocin, bacteria)

POOOO 9 P1966 O. BACTENECIN RFRPPIRRPPIRPPFYPPFRPPIRPPIFPPI 5 (bacs, cow RPPFRPPLGPFP cathelicidin)

POOO1 O P19661, BACTENECIN RRIRPRPPRLPRPRPRPLPFPRPGPRPIP 7 (bac7, cow RPLPFPRPGPRPIPRPLPFPRPGPRPIPRPL cathelicidin)

POO2OO P21564, Mastoparan B LKLKSIWSWAKKWL (MP-B, insect, XXA)

POOOOS P21663, Androp in FIDILDKVENAIHNAAOVGIGFAKPF (insect, fly) : KLINPK

POOOO8 P22226, Cyclic RLCRIWWIRWCR dodecapeptide (cow cathelicidin)

PO12O5 P23826, Lactocin S STPWLASWAWSMELLPTASWLYSDWA. 72 O (XXD3, bacteria)

POO239 P24335, XPF (the GWASKIGOTLGKIAKWGLKELIOPK 721 Xenopsin precursor fragment, African clawed frog)

POO235 P25068, Bovine tracheal NPVSCVRNKGICVPIRCPGSMKOIGTC 722 antimicrobial peptide WGRAWKCCRKK (TAP, cow)

POO 418 P2523 O. CAP18 (rabbit GLRKRLRKFRNKIKEKLKKIGOKIOGF 723 cathelicidin, BBL) WPKLAPRTDY

P25403, MJ-AMP1 OCIGNGGRCNENVG PPYCCSGFCLRO 724 (MAMP1, plant PGOGYGYCKNR defensin)

P25404, MJ-AMP2 CIGNGGRCNENWG d PYCCSGFCLROP 72 (MAMP2, plant NOGYGVCRNR defensin)

POO138 P28310, Cryptdin-3 LRDLWCYCRKRGC K RRERMINGTCRK 726 (Crp3, animal defensin, GHLMYTLCCR alpha, mouse)

POO184 P28794, MBP-1 (plant) RSGRGECRROCLR HEGOPWETOEC 727 MRRCRRRG

POOOSO P29 OO2, Bombinin-like GIGASILSAGKSA KGLAKGLAEHFAN 728 peptide 1 (BLP-1, toad)

POOO51 P29 OO3, Bombinin-like GIGSAILSAGKSA KGLAKGLAEHFAN 729 peptide 2 (BLP-2, toad)

POOO52 P29 OO4, Bombinin-like GIGAAILSAGKSA KGLAKGLAEHF 73 O peptide 3 (BLP-3, XXA, toad) US 8,389,679 B2 101 102 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main.

SEQ ID Effector Structure/Sequence

APOOO53 P29 OO5, Bombinin-like GIGAAILSAGKSIIKGLANGLAEHF 731 peptide 4 (BLP-4, toad)

APOO 634 P2943 O. Pediocin PA-1/ KYYGNGWTCGKHSCSWDWGKATTCII 732 AcH (PedPA1 class IIA NNGAMAWATGGHOGNHKC bacteriocin, bacteria)

APOO2O4. P29559, Nisin Z ITSISLCTPGCKTGALMGCNMIKTATC 733 (lantibiotic, class I NCSIHWSK bacteriocin, bacteria)

APOO13 O P29561, Cecropin C GWLKKLGKRIERIGQHTRDATIOGLGI 734 (insect, fly) AQQAANVAATAR

APOOOO1 P31107, GLWSKIKEWGKEAAKAAAKAAGKAA 73 ADENOREGULIN LGAWSEAW (Dermaseptin B2, Dermaseptin-B2, DRS B2, DRS B2, frog)

APOO228 P31529, Sapecin B LTCEIDRSLCLLHCRLKGYLRAYCSQQ 736 (insect, flesh fly) KVCRCVO

APOO229 P31530, Sapecin C ATCDLLSGIGWOHSACALHCVFRGNR 737 (insect, flesh fly) GGYCTGKGICWCRN

APOO218 P32.195, Protegrin 2 RGGRLCYCRRRFCICW 738 (PG-2, pig cathelicidin)

APOO2.19 P321.96, Protegrin 3 RGGGLCYCRRRFCWCWGR 739 (PG-3, pig cathelicidin)

APOOO73 P32412, Brewinin-1E FLPLLAGLAANFLPKIFCKITRKC 74 O (frog)

APOOO8O P32414, Esculentin-1 GIFSKLGRKKIKNLLISGLKNWGKEWG 74.1 (frog) MDWWRTGIDIAGCKIKGEC

APOOO74 P32423, Brewinin-1 FLPWLAGIAAKWWPALFCKITKKC 742 (frog)

APOOO75 P32424 Brewinin-2 GLLDSLKGFAATAGKGVLOSLLSTAS 743 (frog) CKLAKTC

APOO175 P34084, Macaque DSHEERHHGRHGHHKYGRKFHEKHH 744 histatin (M-Histatin 1, SHRGYRSNYLYDN primate, monkey)

APOOOO6 P35581, Apiidaecin IA GNNRPVYIPOPRPPHPRI 74. (insect, honeybee)

APOOOOf P35581, Apiidaecin IB GNNRPVYIPOPRPPHPRL 746 (insect, honeybee)

APOO 414 P3 619 O Ceratotoxin A SIGSALKKALPWAKKIGKIALPIAKAA 747 (insect, fly) LP

APOO 415 P3 61.91, Ceratotoxin B SIGSAFKKALPWAKKIGKAALPIAKAA 748 (insect, fly) LP

APOO172 P3 61.93, Drosocin GKPRPYSPRPTSHPRPIRW 749 (insect)

APOO 170 P37362, Pyrrhocoricin WDKGSYLPRPTPPRPIYNRN 7 O (insect)

APOO 635 P3.8577, Mesentericin KYYGNGWHCTKSGCSWNWGEAASAG 71 Y105 (MesY1O5, class IHRLANGGNGFW IIA bacteriocin, bacteria)

US 8,389,679 B2 105 106 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOOO43 P461.66, Beta- defensin 8 WRNFWTCRINRGFCVPIRCPGHRROIG 774 (cow) TCLGPOIKCCR

APOOO44 P4 6167. Beta- defensin 9 QGWRNFWTCRINRGFCVPIRCPGHRRO 775 (cow) IGTCLAPOIKCCR

APOOO45 P4 6168 Beta- defensin OGVRSYLSCWGNRGICLLNRCPGRMR 776 10 (cow) OIGTCLAPRVKCCR

APOOO46 P4 6169. Beta- defensin GPLSCRRNGGVCIPIRCPGPMROIGTC 777 11 (cow) FGRPWKCCRSW

APOOO48 P46171, Bovine beta SGISGPLSCGRNGGVCIPIRCPVPMROI 778 defensin 13 (cow) GTCFGRPVKCCRSW

APOO350 P48821, Enbocin PWNIFKEIERAWARTRIDAVISAGPAWR 779 (insect, moth) TWAAATSWAS

APOO173 P4.9112, GNCP-2 RCICTTRTCRFPYRRLGTCLFONRVYT (Guinea pig neutrophil FCC cationic peptide 2)

APOO369 P4993 O, PMAP-23 781 (PMAP23, pig cathelicidin)

APOO370 P49931, PMAP-36 WGRFRRLRKKTRKRLKKIGKWLKWIP 782 (PMAP36, pig PIWGSIPLGCG cathelicidin)

APOO371 P49932, PMAP-37 GLLSRLRDFLSDRGRRLGEKIERIGOKI 783 (PMAP37, pig KDLSEFFOS cathelicidin)

APOO220 P49933, Protegrin 4 RGGRLCYCRGWICFCWGR 784 (PG-4, pig cathelicidin)

APOO221 P49934, Protegrin 5 RGGRLCYCRPRFCWCWGR 78s (PG-5, pig cathelicidin)

APOO346 P5072O, Hyphancin IIID RWKIFKKIERVGONVRDGIIKAGPAIO 786 (Fall webworm, insect) WLGTAKAL

APOO347 P50721, Hyphancin IIIE RWKFFKKIERVGONVRDGLIKAGPAI 787 (Fall webworm, insect) QWLGAAKAL

APOO348 P50722, Hyphancin IIIF RWKWFKKIEKWGRNIRDGWIKAGPAI 788 (Fall webworm, insect) AWWGOAKAL

APOO349 P50723, Hyphancin IIIG RWKWFKKIEKWGRHIRDGWIKAGPAIT 789 (Fall webworm, insect) WWGOATAL

APOO281 P51473, mCRAMP GLLRKGGEKIGEKLKKIGOKIKNFFOK 79 O (mouse cathelicidin; LVPOPEQ derivatives: CRAMP 18)

APOO366 P54228 BMAP-27 GRFKRFRKKFKKLFKKLSPWIPLLHLG 791 (BMAP27, cow cathelicidin, ZZHs, derivatives BMAP-18 and BMAP-15)

APOO367 P54229, BMAP-28 GGLRSLGRKILRAWKKYGPIIWPIIRIG 792 (BMAP28, cow cathelicidin)

APOO 450 P5423 O, Cyclic RICRIIFLRWCR 793 dodecapeptide (sheep cathelicidin)

APOO359 P54684, Lebocin 1/2 DLRFLYPRGKLPWPTPPPFNPKPIYIDM 794 (insect, silk moth) GNRY US 8,389,679 B2 107 108 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

POO360 P55796, Lebocin 3 DLRFLYPRGKLPWPTLPPFNPKPIYIDM 79. (insect, silk moth) GNRY

POO3. Of P55897, Buforin I (toad) AGRGKOGGKVRAKAKTRSSRAGLOF 796 PWGRWHRLLRKGNY

P55897, Buforin II TRSSRAGLOFPWGRV RLLRK 797 (toad)

POO24 O P56226 Caerin 1.1 GLISWLGSWAKHWLPHWWPWIAEHL 798 (frog, ZZHa)

POO241 P56227, Caerin 1.2 GLIGWLGSWAKHWLPHWWPWIAEHL 799 (frog)

POO242 P56228, Caerin 1.3 GLLSVILGSWAOHWLPHVWPVIAEHL (frog)

POO243 P56229, Caerin 1.4 GLISSLSSWAKHWLPHWWPWIAEHL (frog)

POO244 P5623 O. Caerin 1.5 GLISWLGSWWK WIPHWWPWIAEHL (frog)

POO245 P56231, Caerin 1.6 GLFSWLGAWAKHWLPHWWPWIAEK (frog)

POO246 P56.232, Caerin 1.7 GLFKWLGSWAKHLLPHWAPWIAEK 804 (frog)

POO249 P56233, Caerin 2.1 GLVSSIGRALGGLLADVVKSKGOPA 805 (frog)

POO25 O P5 6234, Caerin 2.2 GLVSSIGRALGGLLADVVKSKEOPA 806 (frog)

POO251 P56236, Caerin 2.4 GLVSSIGKALGGLLADVVKTKEOPA 8. Of (frog)

POO252 P56236, Caerin 2.5 GLVSSIGRALGGLLADVVKSKEOPA 808 (frog)

POO253 P56238, Caerin 3.1 GLWOKIKDKASELVSGIVEGVK 809 (frog)

POO254 P56238, Caerin 3.2 GLWEKIKEKASELWSGIWEGWK (frog)

POO255 P5624 O Caerin 3.3 GLWEKIKEKANELWSGIWEGWK (frog)

POO256 P5 6241, Caerin 3.4 GLWEKIREKANELWSGIWEGWK (frog)

POO257 P56242, Caerin 4.1 GLWOKIKSAAGDLASGIVEGIKS (frog)

POO258 P5 6243, Caerin 4.2 GLWOKIKSAAGDLASGIVEAIKS (frog)

POO259 P56244, Caerin 4.3 GLWOKIKNAAGDLASGIVEGIKS (frog)

POO434 P56249 Frenatin 3 GLMSWLGHAWGNWLGGLFKS (frog)

POO272 P56386, Murine beta DOYKCLOHGGFCLRSSCPSNTKLOGT defensin. 1 (m3D-1, CKPDKPNCCKS mouse)

POO368 P56425, BMAP-34 LFRRLRDSIRRGOOKILEKARRIGERI (BMAP34, cow KDIFRG cathelicidin) US 8, 389,679 B2 109 110 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main.

SEQ ID Effector Structure/Sequence

APOO273 P56685, Buthinin SIWPIRCRSNRDCRRFCGFRGGRCTYA 819 (Sahara scorpion) ROCLCGY

APOO282 P56872, SIPCGESCWFIPCTWTALLGCSCKSKWC Cyclopsychotride A (CPT, plant cyclotides, XXC)

APOOO94 P56917, Temporin A FLPLIGRWLSGIL 821 (XXA, frog)

APOOO96 P56918, Temporin C LLPILGNLLNGLI 822 (XXA, frog)

APOOO97 P56920, Temporin E WLPIIGNLLNSLL 823 (XXA, frog)

APOOO98 P56921, Temporin F FLPLIGKWLSGIL 824 (XXA, frog)

APOO1OO P56923, Temporin K LLPNLIKSTL 825 (XXA, frog)

APOO295 P56928, eNAP-2 (horse) EWERKHPLGGSRPGRCPTWPPGTFGHC 826 ACLCTGDASEPKGOKCCSN

APOO 101 P57104, Temporin L FWOWFSKFLGRIL 827 (XXA, frog)

APOOO95 P79874, Temporin B LLPIWGNLLKSLL 828 (XXA, frog)

APOOO99 P79875, Temporin G FFPWIGRILNGIL 829 (XXA, frog)

APOO 413 P80032, Coleoptericin SLOGGAPNFPOPSQQNGGWOWSPDLG 83 O (insect) RDDKGNTRGOIEIONKGKDHDFNAG WGKWIRGPNKAKPTWHWGGTYRR

APOO396 P8 OO54, PR-39 (PR39, RRRPRPPYLPRPRPPPFFPPRLPPRIPPG 831 pig cathelicidin) FPPRFPPRFP

APOO182 P8O154. Insect defensin GFGCPLDOMOCHRHCOTITGRSGGYC 832 SGPLKLTCTCYR

APOO444 P80223, Cortico statin GICACRRRFCLNFEO FSGYCRWNGAR 833 WI (CS-WI) (animal YVRCCSRR defensin, rabbit)

P8023 O, Peptide 3910 RAD TOTYOPYNKDWI KEKIYVLLRRO 834 (pig) AQQAGK

APOO157 P80277, Dermaseptin ALWKTMLKKLGTMAL HAGKAALGA 835 S1 (Dermasept in S1, AADTISOGTO DRS S1, DRS-S1, frog)

APOO158 P80278, Dermaseptin ALWFTMLKKLGTMAL HAGKAALGA 836 S2 (Dermasept in S2, AANTISOGTO DRS S2, DRS-S2, frog)

APOO159 P80279, Dermaseptin ALWKNMLKGIGKLAG KAALGAWKKL 837 S3 (Dermasept in S3 , WGAES DRS S3, DRS-S3, frog)

APOO16 O P80280, Dermaseptin ALWMTLLKKWLKAAA KALNAWLWG 838 S4 (Dermasept in S4, ANA DRS S4, DRS-S4, frog)

APOO161 P80281, Dermaseptin GLWSKIKTAGKSWAKAAAKAAWKAW 839 S5 (Dermaseptin S5, TNAV DRS S5, DRS-S5, frog) US 8,389,679 B2 111 112 TABL 1O-continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOO293 P80282, Dermaseptin AMWKDWLKKIGTWALHAG KAALGA 84 O B1 (DRS-B1, DRS B1, VADTISO frog)

APOO264 P8O389, Chicken GRKSDCFRKSGFCAFLKC PSLTLISGK 841 Heterophil Peptide 1 C SRFYLCCKRIR (CHP1, bird animal

APOO265 P8O39 O. Chicken GRKSDCFRKNGFCAFLKC PYLTLISGL 842 Heterophil Peptide 2 LC (CHP2, bird animal

APOO266 P80391, Turkey GKREKCLRRNGFCAFLKC PTLSWISGT 843 Heterophil Peptide 1 C SRFOVCC (THP1, turkey)

APOO267 P80392, Turkey L FCKRGTCHFGRCPSHLI KWGSCFGFR 844 Heterophil Peptide 2 S CCKWPWDA (THP2, bird, anaimal)

APOO269 P80393, Turkey SCKRGTCHFGRCPSHLI KGSCSGG 845 Heterophil Peptide 3 (THP3 bird animal

APOOO85 P80395, Gaegurin-1 FS IKAGAKFLGKNLL KOGACYAA 846 (Gaegur in 1, frog) s KAS KOC

APOOO86 P80396, Gaegurin-2 IMS IWKDWAKNAAKEAA KGALSTLS 847 (Gaegur in 2, frog) KLIA KTC

APOOO87 P80397, Gaegurin-3 IMS IWKDWAKTAAKEAA KGALSTLS 848 (Gaegurin 3, frog) KLIA KTC

APOOO89 P80399, Gaegurin-5 GA FKWASKWLPSWFCAITKKC 849 (Gaegurin 5, frog)

APOOO90 P804 OO, Gaegurin-6 PL AGLAANFLPTI ICKISYKC 850 (Gaegurin 6, frog)

APOO362 P80408, Metalnikow in I DYRPRPRPPNM 851 (insect)

APOO363 P804O9, Metalnikow in DYRPRPWPRPN 852 IIA (insect)

APOO364 P80410, Metalnikow in DYRPRPWPRNMI 853 IIB (insect)

APOO365 P80411, Metalnikow in DYRPRPWPRPNM 854 III (insect)

APOO 632 P8 O569, Piscicolin 126/ KYYGNGWSCNKNGCTWDWSKAIGIIG 855 Piscicocin Wia NNAAANLTTGGAAGWNKG (PiscV1a, Pisc126, class IIA bacteriocin, bacteria)

APO1 OO3 P80666, Mutacin B FKSWSECTPGCAKTGSFNSYCC 856 Ny266 (bacteria)

APOO276 P8 O710, Clavanin. A 857 (urochordates, sea squirts, and sea pork, tunicate)

APOO277 P8 O711, Clavanin B 858 (Sea squirt, tunicate)

APOO278 P8 O712, Clavanin C 859 (Sea squirt, tunicate)

APOO279 P8 O713, Clavanin D 86 O (Sea squirt, tunicate)

US 8,389,679 B2 119 120 TABL E 1 O - C Ontinued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

POOO55 P82282, Bombinin H1 IIGPWLGMWGSALGGLIKKI 93 O (frog)

POOOS 6 P82284, Bombinin H4 LIGPWLGLWGSALGGLLKKI 931 (frog, XXA, XXD)

POOO57 P82285, Bombinin H5 IIGPWLGLWGSALGGLIKKI 932 (frog, XXD)

POO419 P82286, Bombinin-like GIGASILSAGKSALKGFAKGLAEHFAN 933 peptides 2 (amphibian, toad)

POO 137 P82293, Cryptdin-1 LRDLWCYCRTRGCKRRERMINGTCRK 934 (Crp1, animal defensin, GHLMYTLCCR alpha, mouse)

POO443 P82317, defensin ACYCRIPACLAGERRYGTCFYMGRW 935 RMAD-2 (monkey) WAFCC

POOO12 P82386, Aurein 1.1 KIAESI 936 (amphibian, frog)

POOO14 P82388, Aurein 2.1 KWWGAFGSL 937 (amphibian, frog)

POOO15 P82389, Aurein 2.2 KWWGALGSL 938 (amphibian, frog)

POOO16 P8239 O. Aurein 2.3 KWWGAIGSL 939 (XXA, amphibian, frog)

POOO17 P82391, Aurein 2.4 KWWGTIAGL 94 O (XXA, amphibian, frog)

POOO18 P82392, Aurein 2.5 KWWGAFGSL 941 (XXA, amphibian, frog)

POOO19 P82393, Aurein 2.6 KWIGWIGSL 942 (XXA, amphibian, frog)

POOO2O P82394, Aurein 3.1 KIAGHIAGSI 943 (XXA, amphibian, frog)

POOO21 P82395, Aurein 3.2 KIAGHIASSI 944 (XXA, amphibian, frog)

POOO22 P82396, Aurein 3.3 KIAGHIWSSI 945 (XXA, amphibian, frog)

POO376 P82414, Ponericin G1 GWKDWAK KAGGWLKKKGPGMAKA 946 (ants) ALKAAMQ

POO377 P82415, Ponericin G2 KGKEWLKAKGPGIWKAA 947 (ants)

POO378 P82416, Ponericin G3 KGKEWLKKKGPGIMKAA 948 (ants)

POO379 P82417 Ponericin G4 DFKDWMKTAGEWLKKKGPGILKAA 949 (ants) MAAAT

POO38O P82418 Ponericin G5 GLKDWWKIAGGWLKKKGPGILKAAM 950 (ants) AAATO

POO381 P82419, Ponericin G6 GLWDWLGKWGGLIKKLLP 951 (ants)

POO382 P8242O, Ponericin G7 GLWDWLGKWGGLIKKLLPG 952 (ants)

POO383 P82421, Ponericin L1 LIKELWTKMKGAGKAWLGKIKGLL 95.3 (ants) US 8,389,679 B2 121 122 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

POO384 P82422, Ponericin L2 LIKELWTKIKGAGKAWLGKIKGLL 954 (ants)

POO386 P82423, Ponericin W1 WLGSALKIGAKLLPSWWGLFKKKKQ 955 (ants)

POO387 P82424, Ponericin W2 WLGSALKIGAKLLPSWWGLFOKKKK 956 (ants)

POO388 P82425, Ponericin W3 GIWGTLAKIGIKAVPRVISMLKKKKO 95.7 (ants)

POO389 P82426, Ponericin W4 958 (ants)

POO390 P82427, Ponericin W5 FWGALIKGAAKLIPSVWGLFKKKQ 959 (ants)

POO391 P82428 Ponericin W6 FIGTALGIASAIPAIWKLFK 96.O (ants)

POO303 P82651, Tigerinin-1 FCTMIPIPRCY 961 (frog)

P82652, Tigerinin-2 RWCFAI PLPICH 962 (frog)

POO305 P82653, Tigerinin-3 RVCYAI PLPICY 96.3 (frog)

P82656, Hadrurin GILDTI KSIASKVWNSKTVODLKRKGI 964 (scorpion) NWWANK LGVSPQAA

POO113 P8274 O, GLISGL KKWGKHWAKNWAWSLMDSL 965 RANATUERIN 1.T KCKISG (frog)

POO114 P82741, SMLSWL KNLGKVGLGFVACKINKOC 966 RANATUERIN 1. (Ranatuerin-1, frog)

POO 115 P82742, GLFLDT KGAAKDWAGKLEGLKCKIT 96.7 RANATUERIN 2 GCKLP (Ranatuerin-2, frog)

POO116 P8278O GFID INKLGKTFAGHMLDKIKCTIGT 96.8 RANATUERIN 3 CPPSP (Ranatuerin-3, frog)

POO 117 P82819, ARLAAKWFPSIICSWTKKC 96.9 RANATUERIN 4 (Ranatuerin-4, frog)

POO 405 P82821, FISA ASMLGKFL 97 O RANATUERIN 6 (frog)

P82822, FISA ASMLGKFL 971. RANATUERIN 7 (frog)

POO4. Of P82823, FISA ASFLGKFL 972 RANATUERIN 8 (frog)

P82824, FLFPLITSFLSKWL 973 RANATUERIN 9 (frog)

POO461 P82825, Brewinin-1LA FLPMLAGLAASMWPKLWCLITKKC 974. (frog)

POO462 P82826, Brewinin-1LB FLPMLAGLAASMWPKFWCLITKKC 97. (frog)

US 8,389,679 B2 127 128 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence POO410 P83287, Oncorhyncin SKGKKANKDWELARG III (fish)

POO357 P83305, Japoniclin-1 FFPIGWECKIFKTC (amphibian, frog)

POO358 P83306, Japonic in-2 FGLPMLSILPKALCILLKRKC (amphibian, frog)

POO385 P83312, Parabutoporin FKLGSFLKKAWKSKLAKKLRAKGKE (scorpion) MLKDYAKGLLEGGSEEWPGQ

POO374 P83313, Opistoporin 1 GKWWDWIKSTAKKLWNSEPWKELKN (scorpion) TALNAAKNLWAEKIGATPS

POO375 P83314, Opistoporin 2 GKWWDWIKSTAKKLWNSEPWKELKN (scorpion) TALNAAKNFWAEKIGATPS

POO336 P83327, Histone H2A AERWGAGAPWYL (fish)

POO335 P83338. Histone H6 PKRKSATKGDEPA like protein (fish)

POO 411 P83374, Oncorhyncin II KAWAAKKSPKKAKKPAT (fish)

POO 999 P83375 Serracin-P 43 kDa subunit (bacteria)

POO284 P83376, Dolabellanin SHODCYEALHKCMASHSKPFSCSMKF B2 (sea hare) HMCLQQQ

POO 998 P83378, Serracin-P 23 kDa subunit (bacteriocin, bacteria)

POO129 P834O3, Cecropin GWLKKIGKKIERVGONTRDATVKGLE (insect, moth) WAQQAANVAATWR

POO127 P83413, Cecropin. A RWKWFKKIEKWGRNIRDGWIKAAPAIE (insect, moth) WLGOAKAL

POO372 P83416, Wirescein GKIPIGAIKKAGKAIGKGLRAWNIAST O38 (insect) AHDWYTFFKPKKRH

POO356 P83427, Heliocin ORFIHPTYRPPPOPRRPVIMRA (insect)

POO 409 P83428, Locustin ATTGCSCPOCIIFDPICASSYKNGRRGF (insect) SSGCHMRCYNRCHGTDYFOISKGSKCI

POO339 P83545, Chrysophsin-1 FFGWLIKGAIHAGKAIHGLIHRRRH (Red Sea bream, madai

POO34 O P83546, Chrysophsin-2 FFGWLIRGAIHAGKAIHGLIHRRRH (Red Sea bream, madai

POO341 P83547, Chrysophsin-3 FIGLLISAGKAIHDLIRRRH (Red Sea bream, madai

P84763, Thuricin-S DWTAWSALWAAACSWELL (bacteria)

POOSS3 P84868, Sesquin (plant, KTCENLADTY ZZHp)

POO132 Q06589, Cecropin 1 GWLKKIGKKIERVGOHTRDATIOTIAV (insect, fly) AQQAANVAATAR

POO135 Q06590, Cecropin 2 GWLKKIGKKIERVGOHTRDATIOTIGV (insect fly) AQQAANWAATLK

US 8,389,679 B2 131 132 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence POO309 Ref, Human KS-27 KSKEKIGKEFKRIVORIKDFLRNLVPR Of O (KS27 from LL-37)

POO344 Ref, Apiidaecin II GNNRPIYIPOPRPPHPRL O71 (honeybee, insect)

POO 424 Ref, XT1 (frog) GFLGPLLKLAAKGVAKVIPHLIPSRQQ O72

POO 425 Ref, XT 2 (frog) GCWSTWLGGLKKFAKGGLEAIWNPK O73

POO426 Ref, XT 4 (frog) GWFLDALKKFAKGGMNAWLNPK O74

POO 427 Ref, XT 7 (frog) GLLGPLLKIAAKWGSNLL Ofs

POO431 Reft human LLP 1 RVIEWVOGACRAIRHIPRRIROGLERIL O76

POO432 Ref, human LLP RIAGYGLRGLAWIIRICIRGLNLIFEIIR O77

POO447 Ref, Anoplin (insect) GLLKRIKTLL O78

POO474 Ref, Piscidin 3 (fish) FIHHIFRGIWHAGRSIGRFLTG O79

POO481 Ref, Kaliocin-1 FFSASCVPGADKGOFPNLCRLCAGTG (synthetic) ENKCA

POO482 Ref, Thionin mutation KSCCRNTWARNCYNWCRLPGTISREIC (synthetic) AKKCRCKIISGTTCPSDYPK

POO484 Ref, Stomoxyn (insect, RGFRKHFNKLWKKWKHTISETAHWAK fly) DTAWIAGSGAAWWAAT

POO486 Ref, Cupiennin 1b GFGSLFKFLAKKVAKTWAKOAAKOG (spider) AKYIANKOME

POO487 Ref, Cupiennin 1c GFGSLFKFLAKKVAKTWAKOAAKOG (spider) AKYIANKOTE

POO 488 Ref, Cupiennin 1D GFGSLFKFLAKKVAKTWAKOAAKOG (spider) AKYWANKHME

POO 489 Ref, Hipposin (fish) SGRGKTGGKARAKAKTRSSRAGLOFP O86 WGRVHRLLRKGNYAHRWGAGAPWYL

POO 923 Ref, Carnobacteriocin AISYGNGVYCNKEKCWVNKAENKOA B1 (XXO, class IIa ITGIWIGGWASSLAGMGH bacteriocin, bacteria)

POO496 Ref, HP 2-2O (synthetic) AKKVFKRLEKLFSKIONDK O88

POO497 Ref, Maximin H5 (toad) ILGPWLGLWSDTLDDWIGIL

POO 498 Ref, rCRAMP (rat GLVRKGGEKEGEKLRKIGOKIKEFFO cathelicidin) KLALEIEQ

POOSOO Ref, S9-P18 (synthetic) KWKLFKKISKFLHLAKKF

POOSO1 Ref, L9-P18 (synthetic)

POOSO2 Ref, Clavaspirin (sea FLRFIGSWIHGIGHLWHHIGWAL squirt, tunicate)

POOSO3 Ref, human P-113D

POOSO4 Ref, human MUC7 20 LAHOKPFIRKSYKCLHKRCR Mer

POOSOf Ref, Nigrocin 2 (frog) GLISKWLGWGKKWICGWSGLC O96

POOSO 8 Ref, Nigrocin 1 (frog) GLLDSIKGMAISAGKGALONLLKVAS CKLDKTC

POOSO 9 Ref, human Calcitermin WAIALKAAHYHTHKE US 8,389,679 B2 133 134 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOO510 Ref, Dicynthaurin (sea ILOKAVLDCLKAAGSSLSKAAITAIYN O99 peach) KIT

APOO511 Ref, KIGAKI KIGAKIKIGAKIKIGAKI OO (synthetic)

APOO516 Ref, Lycotoxin. I IWLTALKFLGKHAAKHLAKOOLSKL O1 (spider)

APOO517 Ref, Lycotoxin II KIKWFKTMKSIAKFIAKEOMKKHLGGE O2 (spider)

APOO518 Ref, Ib-AMP3 (plant OYRHRCCAWGPGRKYCKRWC O3 defensin, balsam)

APOO519 Ref, Ib-AMP4 (plant EWGRRCCGWGPGRRYCRRWC O4 defensin, balsam)

APOO521 Ref, DhvarA (synthetic) KLIFSLRKY

APOO522 Ref, Dhvar5 (synthetic) KKRKKRKY

APOOS25 Ref, Maximin H2 (toad) SMWGSALGGLIKKI

APOO526 Ref, Maximin H3 (toad) ILGPW GLWGNALGGLIKKI

APOO527 Ref, Maximin H4 (toad) ILGPWISKIGGWLGGLLKNL

APOOS28 Ref, Anionic peptide DDDDD 1O SAAP (sheep)

APOO530 Ref, Lantibiotic Ericin WLSKS LCTPGCITGPLOTCYLCFPTFA 11 A (bacteria)

APOO531 Ref, Kenojeinin I (sea PKWGGRLSGKAPLAAKTHRRL 12 skate)

APOO532 Ref, Lunatus in (plant, KTCEN ADTFRGPCFATSNC 13 ZZHp)

APOOS33 Ref, Fallaxin (frog) KGAAKDIAGHLASKWMNKL 14

APOO534 Ref, Tu-AMP 2 KSCCRNTTARNCYNWCRIPG 15 (TuAMP2, thionin-like antimicrobial peptides, plant defensin, tulip)

APOOS35 Ref, Pilosulin 1 (Myr b GLGSWFGRLARILGRWIPKWAKKLGPK 1116 I) (Australian ants) VAKVLPKVMKEAIPMAVEMAKSOEE

APOO536 Ref, Luxurios in (insect) SVRTODNAVNROIFGSNGPYRDFOLS 1117 DCYLPLETNPYCNEWOFAYHWNNAL MDCERAIYHGCNRTRNNFITLTACKN OAGPICNRRRH

APOO537 Ref, SAMP H1 (fish, AEWAPAPAAAAPAKAPKKKAAAKPK 1118 Atlantic salmon) KAGPS

APOO538 Ref, Halocidin (dimer WLNALLHHGLNCAKGWLA 1119 Hall18 + Hall15) (tunicate)

APOO539 Reft AOD (American GFGCPWNRYOCHSHCRSIGRLGGYCA 112O oyster defensin, animal GSLRLTCTCYRS defensin)

APOO540 Ref, Pentadactylin GLL.DTLKGAAKNWWGSLASKWMEKL 1121 (frog)

APOO541 Ref, Polybia-MPI IDWKKLLDAAKOIL 1122 (insect, social Wasp) US 8,389,679 B2 135 136 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main.

SEQ ID Effector Structure/Sequence APOO542 Ref, Polybia-CP (insect, ILGTILGLLKSL 1123 social Wasp)

APOO543 Ref, Ocellatin-1 (XXA, GWWDILKGAGKDLLAHLWGKISEKW 1124 frog)

APOO544 Ref, Ocellatin-2 (XXA, GVLDIFKDAAKOILAHAAEKOI 1125 frog)

APOO545 Ref, Ocellatin-3 (frog) GVLDILKNAAKNILAHAAEOI 1126

APOO548 Ref, CMAP 27 (chicken RFGRFLRKIRRFRPKVTITIOGSARFG 1127 myeloid antimicrobial peptide 27, bird cathelicidin, chicken cathelicidin)

APOOSSO Ref, Tu-AMP-1 KSCCRNTWARNCYNWCRIPGTPRPVC 1128 (TuAMP 1, thionin-like AATCDCKLITGTKCPPGYEK antimicrobial peptides, plant defensin, tulip)

APOO551 Ref, Combi-2 FRWWHR 1129 (synthetic)

APOO552 Ref, Maximin 9 (frog) GIGRKFLGGWKTTFRCGWKDFASKHLY 1130

APOO554 Reft S1 moricin (insect) GKIPWKAIKKAGAAIGKGLRAINIAST 1131 AHDWYSFFKPKHKKK

APOO555 Ref, Parasin I (catfish) KGRGKOGGKVRAKAKTRSS 1132

APOO556 Ref, Kassinatuerin-1 GFMKYIGPLIPHAWKAISDLI 1133 (frog)

APOO557 Ref, Fowlicidin-1 RWKRWWPLWIRTWIAGYNLYRAIKKK 1134 (chCATH-1, bird cathelicidin, chicken cathelicidin)

APOO559 Ref, Eryngiin ATRWWYCNRRSGSWWGGDDTWYYEG 35 (mushroom, fungi)

APOOS60 Ref, Dendrocin (plant, TTLTLHNLCPYPWWWLWTPNNGGFPII 36 bamboo) DNTPWWLG

APOO561 Ref, Coconut antifungal EOCREEEDDR 37 peptide (plant)

APOO562 Ref, Pandinin 1 (African GKVWDWIKSAAKKIWSSEPVSOLKG 38 scorpion) OVLNAAKNYWAEKIGATPT

APOOS63 Ref, White cloud bean KTCENLADTFRGPCFATSNCDDHCKN 39 defensin (plant KEHLLSGRCRDDFRCWCTRNC defensin)

APOO564 Ref, Dybowskin-1 FLIGMTHGLICLISRKC 4 O (frog)

APOOS65 Ref, Dybowskin-2 FLIGMTOGLICLITRKC 41 (frog)

APOO566 Ref, Dybowskin-3 GLFDWWKGVLKGWGKNWAGSLLEOL 42 (frog) KCKLSGGC

APOO567 Ref, Dybowskin- 4 WWPLGLWICKALKIC 43 (frog)

APOO568 Ref, Dybowskin-5 GLFSWWTGWLKAWGKNWAKNWGGSL 44 (frog) LEOLKCKKISGGC

APOO569 Ref, Dybowskin- 6 FLPLLLAGLPLKLCFLFKKC 45 (frog) US 8,389,679 B2 137 138 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence POOSFO Ref, Pleurain-A1 (frog) SIITMTKEAKLPQLWKOIACRLYNTC 46

POO571 Ref, Pleurain-A2 (frog) SIITMTKEAKLPQSWKOIACRLYNTC 47

POOS74 Ref, Esculentin-IGRa GLFSKFAGKGIKNLIFKGWKHIGKEWG 48 (frog) MDWIRTGIDWAGCKIKGEC

POOsfs Ref, Brewinin-2GRa GLLDTFKNLALNAAKSAGWSWLNSLS 49 (frog) CKLSKTC

POO576 Ref, Brewinin-2GRb LGTWKNLLIGAGKSAAQSVLKTLS SO (frog) KLSNDC

POOff Ref, Brewinin-2GRc GLFTLIKGAAKLIGKTWAKEAGKTGLE 51 (frog) LMACKITNOC

POO578 Ref, Brewinin-1GRa FLPLLAGLAANFLPKIFCKITKKC 52 (frog)

POO579 Ref, Nigrocin-2GRa GLISGILGAGKHIWCGLSGIC 53 (frog)

POOS8 O Ref, Nigrocin-2GRb GLFGKILGWGKKWICGLSGMC 54 (frog)

POO581 Ref, Nigrocin-2GRc GLISGILGAGKNIWCGLSGIC 55 (frog)

POO582 Ref, Brewinin-2GHa GFSSLFKAGAKYLLKSVGKAGAQOLA 56 (frog) CKAANNCA

POO583 Ref, Brewinin-2GHb GWITDALKGAAKTWAAELLRKAHCKL st (frog) TNSC

POOS84 Ref, Guentherin (frog) WIDDLKKWAKKWRRELLCKKHHKKLN 58

POO585 Ref, Brewinin-2GHo SIWEGIKNAGKGFLWSILDKWRCKWA 59 (frog) GGCNP

POO586 Ref, Temporin-GH FLPLLFGAISHLL 60 (frog)

POO587 Ref, Brewinin-2TSa GIMSLFKGVLKTAGKHWAGSLVDOLK 61 (frog) CKITGGC

POO588 Ref, Brewinin-1TSa GSIWGALASALPSLISKIRN 62 (frog)

POO589 Ref, Temporin-1TSa GALAKIISGIF 63 (frog)

POO593 Ref, Brewinin-1CSa PILAGLAAKIWPKLFCLATKKC 64 (frog)

POO594 Ref, Temporin-1CSa PIWGKLLSGLL 65 (frog)

POO595 Ref, Temporin-1CSb PIIGKLLSGLL 66 (frog)

POO596 Ref, Temporin-1CSc PLWTGLISGLL 67 (frog)

POO597 Ref, Temporin-1CSd NFLGTLWNLAKKIL 68 (frog)

POO598 Ref, Temporin-1SPb FLSAITSLLGKLL 69 (frog)

POO599 Ref, Brewinin-2-related GIWDTIKSMGKVFAGKILONL 70 (frog)

POO 600 Ref, Odorranain-HP GLILRASSWWGRKYYWDLAGCAKA 71. (frog)

US 8,389,679 B2 141 142 TABLE 1 O - C Ontinued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

POO 639 Ref, Citrop in 2. 1.3 GLIGSIGKALGGLLVDVLKPKLOAAS 196 (frog)

POO 64 O Ref, Maculatin 1.3 GLIGLLGSWWSHWWPAIWGHF 197 (frog)

POO 641 Ref, Pardaxin 1 GFFALIPKIISSPLFKTLLSAWGSALSSS 198 (Pardaxin P-1, Pardaxin GEOE P1, Pa1, flat fish)

POO 642 Ref, Pardaxin 2 GFFALIPKIISSPIFKTLLSAWGSALSSS 199 (Pardaxin P-2, Pardaxin GGOE P2, Pa2, flat fish)

POO 643 Ref, Pardaxin 3 GFFAFIPKIISSPLFKTLLSAWGSALSSS 2 OO (Pardaxin P-3, Pardaxin GEOE P3, Pa3 flat fish)

POO 645 Ref, Pardaxin 5 GFFAFIPKIISSPLFKTLLSAWGSALSSS (Pardaxin P-5 Pardaxin GDOE P5, Pa5 flat fish)

POO647 Ref, Brewinin-1PLb FLPLIAGLAANFLPKIFCAITKKC (frog)

POO 648 Ref, Brewinin-1PLuc FLPWIAGWAAKFLPKIFCAITKKC (frog)

POO649 Ref, Esculentin-1PLa GLFPKINKKKAKTGWFNIIKTWGKEAG (frog) MDLIRTGIDTIGCKIKGEC

POO 650 Ref, Esculentin-1PLb GIFTKINKKKAKTGWFNIIKTIGKEAG (frog) MDWIRAGIDTISCKIKGEC

POO651 Ref, Esculentin-2PLa GLFSILKGWGKIALKGLAKNMGKMGL (frog) DLWSCKISKEC

POO652 Ref, Ranatuerin-2PLa GIMDTVKNVAKNLAGOLLDKLKCKIT (frog) AC

POO653 Ref, Ranatuerin-2PLb GIMDTWKNAAKDLAGOLLDKLKCRIT (frog) GC

POO654 Ref, Ranatuerin-2PLuc GLLDTIKNTAKNLAWGLLDKIKCKMT 209 (frog) GC

POO 655 Ref, Ranatuerin-2PLud GIMDSVKNVAKNIAGOLLDKLKCKIT (frog) GC

POO 656 Ref, Ranatuerin-2PLe GIMDSVKNAAKNLAGOLLDTIKCKIT (frog) AC

POO657 Ref, Ranatuerin-2PLif GIMDTVKNAAKDLAGOLDKLKCRITGC (frog)

POO658 Ref, Temporin-1PLa FLPLWGKILSGLI (frog)

POO 659 Ref, Ranatuerin 5 (frog) FLPIASLIGKYL

POO 661 Ref, Esculentin-2L GILSLFTGGIKALGKTLFKMAGKAGA (frog) EHLACKATNOC

POO 662 Ref, Esculentin-2B GLFSILRGAAKFASKGIGKDLTKLGW (ESC2B-RANBE, frog) DLVACKISKOC

POO 663 Ref, Esculentin-2P GFSSIFRGWAKFASKGIGKDLARLGW (frog) NLVACKISKOC

POO 664 Ref, Peptide A1 (frog) FLPAIAGILSQLF

POO 665 Ref, Peptide B9 (frog) FLPLIAGLIGKLF US 8,389,679 B2 143 144 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence POO 666 Ref, PG-L (frog) EGGGPOWAVGHFM 22O

POO 667 Ref, PG-KI (frog) EPHPDEFWGLM 221

POO 668 Ref, PG-KII (frog) EPNPDEFWGLM 222

POO 669 Ref, PG-KIII (frog) EPHPNEFWGLM 223

POO670 Ref, PG-SPI (frog) EPNPDEFFGLM 224

POO 660 Ref, Pandinin 2 (African FWGALAKGALKLIPSLFSSFSKIKD 225 scorpion)

POO671 Ref, PG-SPII (frog) EPNPNEFFGLM 226

POO673 Ref, Lantibiotic Ericin S WKSESVCTPGCVTGVLOTCFLQTITC 227 (bacteria NCHISK

POO674 Ref, Lantibiotic Ericin VLSKSLCTPGCITGPLOTCYLCFPTFA 228 A (bacteria KC

POO675 Ref, Human beta FELDRICGYGTARCRKKCRSOEYRIGR 229 defensin 4 (HBD-4, CPNTYACCLRKWDESLLNRTKP HBD4, human defensin)

POO676 Ref, RL-37 (RL37, RLGNFFRKVKEKIGGGLKKWGOKIKD 23 O monkey cathelicidin) FLGNLWPRTAS POO677 Ref, CAP11 (Guinea pig GLRKKFRKTRKRIOKLGRKIGKTGRK 231 cathelicidin) WWKAWREYGOIPYPCRI

POO678 Ref, Canine cathelicidin RLKELITTGGOKIGEKIRRIGORIKDFF 232 (K9CATH) (dog) KNLOPREEKS

POO679 Ref, Esculent in 2WEb GLFSILKGWGKIAIKGLGKNIGKMGL 233 (frog) DLWSCKISKEC

POO 680 Ref, SMAP-34 (sheep GLFGRLRDSLORGGOKILEKAERIWC 234 cathelicidin) K I K D I R

POO 681 Ref, OaBac5 (sheep RFRPPIRRPPIRPPFRPP R d PWRPPIRPP 235 cathelicidin) FRPPFRPPIGPFP

POO 682 Ref, OaBac6 (sheep RRLRPRHOHFPSERPWPKPLPLPLPRP 236 cathelicidin) GPRPWPKPLPLPLPRPGLRPWPKPL

POO 683 Ref, OaBac7.5 (sheep RRLRPRRPRLPRPRPRPRPRPRSLPLPR 237 cathelicidin) POPRRIPRPILLPWRPPRPIPRPOIOPIPR

POO 684 Ref, OaBac11 (sheep RRLRPRRPRLPRPRPRPRPRPRSLPLPR 238 cathelicidin) PKPRPIPRPLPLPRPRPKPIPRPLPLPRP RPRRIPRPLPLPRPRPRPIPRPLPLPOPO PSPIPRPL

POO 685 Ref, Ranatuer in 2WEb GIMDTWKGWAKTWAASLLDKLKCKIT 239 (frog) GC

POO 686 Ref, eCATH-1 (horse KRFGRLAKSFLRMRILLPRRKILLAS 24 O cathelicidin)

POO 687 Ref, eCATH-2 (horse KRRHWFPLSFOEFLEOLRRFRDOLPFP 241 cathelicidin)

POO 688 Ref, eCATH-3 (horse KRFHSVGSLIORHOOMIRDKSEATRH 242 cathelicidin) GIRIITRPKLLLAS

POO 689 Ref, Prophenin-1 (pig AFPPPNWPGPRFPPPNFPGPRFPPPNFP 243 cathelicidin) PRFPPPNFPGPRFPPPNFPGPPFPPPIFP PWFPPPPPFRPPPFGPPRFP

POO690 Ref, Prophenin-2 (pig AFPPPNWPGPRFPPPNWPGPRFPPPNFP 244 cathelicidin) PRFPPPNFPGPRFPPPNFPGPPFPPPIFP GPWFPPPPPFRPPPFGPPRFP US 8,389,679 B2 145 146 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOO 691 Ref, HFIAP-1 (hagfish 245 cathelicidin)

APOO 692 Ref, HFIAP-3 (hagfish 246 cathelicidin)

APOO 693 Ref, Trout cath (fish RICSRDKNCVSRPGWGSIIGRPGGGSLI 247 cathelicidin) GRPGGGSWIGRPGGGSPPGGGSFNDEF IRDHSDGNRFA

APOO 694 Ref, MRP (melittin AIGSILGALAKGLPTLISWIKNR 248 related peptide)

APOO695 Ref, Temporin-1 TGa FLPILGKLLSGIL 249 (frog)

APOO 696 Ref, Dahlein 1.1 (frog) GLFDIIKNIWSTL 250

APOO697 Ref, Dahlein 1.2 (frog) GLFDIIKNIFSGL 251 APOO 698 Ref, Dahlein 4.1 (frog) GLWOLIKDKIKDAATGFWTGIOS 252

APOO699 Ref, Dahlein 4.2 (frog) GLWQFIKDKLKDAATGLVTGIOS 253

APOOf OO Ref, Dahlein 4.3 (frog) GLWOFIKDKFKDAATGLVTGIOS 254 APOOf O1 Ref, Dahlein 5.1 (frog) GLIGSIGNAIGAFIANKLKP 255

APOOf O2 Ref, Dahlein 5. 2 (frog) GLIGSIGNAIGAFIANKLKPK 256

APOOf O3 Ref, Dahlein 5.3 (frog) GLLASLGKWIGGYLAEKLKP 27

APOO704 Ref, Dahlein 5. 4 (frog) GLIGSIGKWIGGYLAEKLKPK 258 APOOf OS Ref, Dahlein 5.5 (frog) GLLASLGKWIGGYLAEKLKPK 259

APOOf O6 Ref, Dahlein 5.6 (frog) GLLASLGKWFGGYLAEKLKPK 26 O

APOO709 Ref, Mytilus defensin GFGCPNDYPCHRHCKSIPGRAGGYCG 261 (mytilin) A. (mollusc) GAHRLRCTCYR

APOO711 Ref, Mussel defensin GFGCPNNYACHOHCKSIRGYCGGYC 262 MGD2 AGWFRLRCTCYRCG

APOO712 Ref, scorpion defensin GFGCPLNOGACHRHCRSIRRRGGYCA 263 GFFKQTCCYRN

APOO713 Ref, Androctonus GFGCPFNOGACHRHCRSIRRRGGYCA 264 defensin GLFKQTCTCYR

APOO714 Ref, Orinthodoros GYGCPFNOYOCHSHCSGIRGYKGGYC 265 defensin A (soft ticks) KGTFKOTCKCY

APOO715 Ref, VaD1 (plant RTCMKKEGWGKCLIDTTCAHSCKNR 266 defensin) GYGGNCKGMTRTCYCLVNC

APOO722 Ref, Cryptonin (insect, GLINGLALRLGKRALKKIIKRLCR 267 cicada)

APOO723 Ref, Decoralin (insect) SLLSLLRKLIT 268

APOO724 Ref, RTD-2 (rhesus RCLCRRGWCRCLCRRGWC 269 theta-defensin-2, minidefensin, XXC BBS lectin, ZZHa)

APOO725 Ref, RTD-3 (rhesus RCICTRGFCRCICTRGFC 1270 theta-defensin-3, minidefensin, XXC BBS lectin, ZZHa)

APOO726 Ref, Combi-1 1271 (synthetic) US 8,389,679 B2 147 148 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOOf 48 Ref, Gm pro-rich pept1 DIOIPGIKKPTHRDIIIPNWNPNVRTOP 272 (insect) WORFGGNKS

APOOf 49 Ref, Gm anionic pept 1 EADEPLWLYKGDNIERAPTTADHPILP 273 (insect) SIIDDWKLDPNRRYA

APOO750 Ref, Gm pro-rich pept 2 EIRLPEPFRFPSPTWPKPIDIDPILPHPWS 274 (insect) PROTYPIIARRS

APOO752 Ref Gm defensin-like DKLIGSCWWGATNYTSDCNAECKRR 27s peptide (insect) GYKGGHCGSFWNWNCWCEE

APOO753 Ref Gm VOETOKLAKTVGANLEETNKKLAPOI 276 apolipophoricin (insect) KSAYDDFWKQAQEWQKKLHEAASKO

APOO754 Ref, Gm anionic pept2 ETESTPDYLKNIOOOLEEYTKNFNTOV 277 (insect) ONAFDSDKIKSEVNNFIESLGKILNTE KKEAPK

APOO755 Ref, Gm cecropin D ENFFKEIERAGORIRDAIISAAPAVETL 278 like pept, insect AQAOKIIKGGD

APOO756 Ref, Dermaseptin-B6 ALWKDILKNAGKAALNEINOLVNQ 279 (DRS-B6, DRS B6, XXA, frog)

APOO759 Ref, Phylloseptin-O1 FLSLIPHAINAVSTLWHHSG 28O (PLS-O1, Phylloseptin 4, PS- 4, XXA, frog)

APOO760 Ref, Phylloseptin-O2 FLSLIPHAINAWSAIAKHS 281 (PLS-O2, Phylloseptin 5, PS-5, XXA, frog)

APOO761 Ref, Phylloseptin- 6 SLIPHAINAWSAIAKHF 282 (Phylloseptin-H4, PLS H4, PS-6, XXA, frog)

APOO762 Ref, Phylloseptin-7 FLSLIPHAINAWSAIAKHF 283 (Phylloseptin-H5, PLS H5, PS-7, XXA, frog)

APOO763 Ref, Dermaseptin DPh-1 GLWSTIKNWGKEAAIAAGKAAL.GAL 284 (XXA, frog)

APOOf 64 Ref, Dermaseptin-S9 GLRSKIWLWWLLMIWOESNKFKKM 285 (DRS-S9, DRS S9, frog)

APOO765 Ref, Human salvic MHDFWWLWWLLEYIYNSACSWLSATS 286 SVSSRVLNRSLOVKVVKITN

APOO766 Ref, Gassericin. A IYWIADQFGIHLATGTARKLLDAMAS 287 (XXC, XXD2 class IV GASLGTAFAAILGWTLPAWALAAAGA bacteriocin, Gram LGATAA positive bacteria)

APOO767 Ref, Circularin A (XXC WAGALGWOTAAATTIVNVILNAGTLV 1288 class IV bacteriocin, TWLGIIASIASGGAGTLMTIGWATFKA Gram-positive bacteria) TWOKLAKOSMARAIAY

APOO768 Ref, Closticin 574 PNWTKIGKCAGSIAWAIGSGLFGGAK 1289 (bacteria) LIKIKKYIAELGGLOKAAKLLVGATT WEEKLHAGGYALINLAAELTGVAGIQ ANCF

APOO769 Ref, Caer in 1.1.1 (XXA, GLLGAMFKWASKWLPHWWPAITEHF 1290 frog)

APOOff O Ref, Maculatin 1.4 GLLGLLGSVVSHVLPAITOHL 1291 (XXA, frog)

APOOff1 Ref, Magainin 1 (frog) GIGKFLHSAGKFGKAFWGEIMKS 1292 US 8,389,679 B2 149 150 TABL 1 O - C Ontinued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence POO772 Ref, Oxyopinin 1 RGLAKL KIGLKSFARWLKKWLPKA. 293 (spider) A. KAGKALAKSMADENAIROONQ

POO773 Ref, Oxyopinin 2a KILRSIAKVFKGVGKVRKOF 294 (spider) KTASDLD KNO

POO774 Ref, Oxyopinin 2b 295 (spider) KEASDLD KNO

POOffs Ref, Oxyopinin 2c KLSGIS KVLRAIAKFFKGVGKARKO 296 (spider) KEASDL

POO776 Ref, Oxyopinin 2d 297 (spider) KTASDLD KNO

POO777 Ref, NRC-1 (XXA, fish, KGRWLE RIGKAGGIIIGGALDHL 298 gene predicted)

POO778 Ref, N RC-2 (XXA, fish, LRRIGKGWKIIGGAALDHL 299 gene predicted)

POO779 Ref, RC-3 (XXA, fish, RRKRKWLRRIGKGWKIIGGAALDHL 3 OO gene redicted)

POO781 Ref, N RC-5 (XXA, fish, LGALIKGAIHGGRFIHGMIQNHH 3 O1 gene predicted)

POO782 Ref, RC-6 (XXA, fish, GWGSI FKHGRHAAKHIGHAAWNHYL 3 O2 gene predicted)

POO783 Ref, NRC-7 (XXA, fish, FKKATHWGKHWGKAALTAYL 3O3 gene predicted)

POO784 Ref, NRC-10 (XXA, FFRLL 3O4. fish, gene predicted)

POO785 Ref, NRC-11 (XXA, FR KAKKWGKTWGGLALDHYL 3. OS fish, gene predicted)

POO786 Ref, NRC-12 (XXA, RAKKWGKTWGGLAWDHYL 3 O6 fish, gene predicted)

POO787 Ref, NRC-13 (XXA, GWRLLLK KAEWKTWGKLALKHYL 3. Of fish, gene predicted)

POO788 Ref, NRC-14 (XXA, AGWGSIF KHIFKAGKFIHGAIOAHND 3O8 fish, gene predicted)

POO789 Ref, NRC-15 (XXA, KLGLHGIGLLHLHL fish, gene predicted)

POO790 Ref, NRC-16 (XXA, KGAKHLGOAAIK fish, gene predicted)

POO791 Ref, NRC-17 (XXA, KGAKHLGOAAIKGLAS fish, gene predicted)

POO792 Ref, NRC-19 (XXA, FIGLL fish, gene predicted)

POO793 Ref, Bombinin H2 I IGPWLGLWGSALGGLIKKI (XXA, frog)

POO794 Ref, Bombinin H3 (frog, I IGPWLGMWGSALGGLIKKI XXD, XXA)

POO795 Ref, Bombinin H7 (frog, ILGPILGLWSNALGOLL XXD, XXA)

POO796 Ref, Bombinin GH-1L. I IGPWLGLWGKPLESLLE (XXA, toad)

POO797 Ref, Bombinin GH-1D I IGPWLGLWGKPLESLLE (toad, XXD, XXA) US 8,389,679 B2 151 152 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

POO807 Ref, Enterocin E-76O NRWYCNSAAGGWGGAAGCWLAGYW 3.18 (bacteriocin, bacteria) GEAKENIAGEWRKGWGMAGGFTHNK ACKSF PGSGWASG

POO808 Ref, hepcidin (fish) CRFCC RCCPRMRGCGLCCRF 319

POO809 Ref, hepcidin TH1-5 GIKCR FCCGCCTPGICGVCCRF 32O (fish)

POO810 Ref, hepcidin TH2-3 QSHLS LCRWCCNCCRSNKGC 321 (fish)

POO811 Ref, human LEAP-2 RGWSLRPIGASCRDDSECITRL 322 CRKRRCSLSWAOE

POO812 Ref, Enkelytin (cow) FAEPL PSEEEGESYSKEPPEMEKRYGG 323 FM

POO732 Ref, Spheniscin-1 SFGLCR LRRGSCAHGRCRFPSIPIGRCS 324 (Sphe-1, avian defensin) RFVOCC RRVW

POO733 Ref, Organgutan LGDF RKAREKIGEE RIVORIKDFL 3.25 ppyLL-37 (Great Ape, RTES primate cathelicidin)

POO734 Ref, Gibbon himdSL-37 SIGNF RKARKKIGEE RIVORIKDF 326 (hylobatidae, primate LOHLIP RTEA cathelicidin)

POO735 Ref, pobRL-37 RKAKKKIGRGLKKIGOKIKDF 327 (cercopithecidae, RTES primate cathelicidin) POO736 Ref, caRL-37 (primate RIGDI LOKAREKIEGGLKKLWOKIKDF 328 cathelicidin) FGKFAP RTES

POO737 Ref, Plasticin PBN2KF GLWTSL IKGAGKLIGGLFGSWTG 329 (XXA, DRP-PBN2, frog)

POO738 Ref, Plasticin ANCKF GLWTG LKTAGKLIGDLFGSLTG 330 (XXA, synthetic)

POO739 Ref, Plasticin PD36KF LKTAGKLIGNLFGSLSG 331 (XXA, synthetic)

POOf 40 Ref, Plasticin PD36K LKTAGKLIGNLWGSLSG 332 (XXA, synthetic)

POOf 41 Ref, Chicken PITYL DAILAAVRLLNQRISGPCILRLR 333 cathelicidin-B1 (bird EAQPR PGWVGTLORRREVSFLVEDGP cathelicidin) CPPGV DCRSCEPGALOHCVGTVSIEO OPTAE LRCRPLRPO

POOf 42 Ref, Chicken gallinacin MRI LYLLLSVILFWVLQGWAGOPYFSSP 334 4 (Gal. 4) IHACRYORGVCIPGPCRWPYYRVGSC GSG

POOf 43 Ref, Chicken gallinacin MKI CFFIWLFWAWHGAWGFSRSPRYH 335 7 (Gal 7) MOCGY RGTFCTPGKCPYGNAYLGLC RPKYSCCRWL

POO744 Ref, Chicken gallinacin PLLFAWLLLMLRAEPGLSLARGL 336 9 (Gal 9) PODCE RRGGFCSHKSCPPGIGRIGLCS KED FCCRSRWYS

POOf 45 Ref, Chicken LEAP-2 MTP FWRGWSLRPWGASCRDNSECITM 337 (cLEAP-2) LCR KNRCFLRTASE

POO814 Ref, Caerulein GLGSI GKILNWAGKWGKTIGKWADA 338 precursor-related KE fragment Ea (CPRF-Ea, frog) US 8,389,679 B2 153 154 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main.

SEQ ID Effector Structure/Sequence

APOO815 Ref, Caerulein GLGSFLKNAIKIAGKWGSTIGKWADAI 1339 precursor-related GNKE fragment Eb (CPRF-Eb, frog)

APOO816 Ref, Caerulein GLGSFFKNAIKIAGKWGSTIGKWADAI 134 O precursor-related GNKE fragment Ec (CPRF-Ec, frog)

APOO 817 Ref, Temporin-1Oa FLPLLASLFSRLL 341 (frog)

APOO818 Ref, Temporin-1Ob FLPLIGKILGTIL 342 (frog)

APOO819 Ref, Temporin-1Oc FLPLLASLFSRLF 343 (frog)

APOO82O Ref, Temporin-1Od FLPLLASLFSGLF 344 (frog)

APOO821 Ref, Brevinin-2 0a (frog) LFNWFKGLKTAGKHWAGSLLNOLK 345 KWSGGC

APOO822 Ref, Brevinin-2Ob (frog) IFNWFKGALKTAGKHWAGSLLNOLK 346 KWSGEC

APOO824 Ref, Temporin-1Gb SILPTIWSFLSKFL 347 (XXA, frog)

APOO 825 Ref, Temporin-1Gc SILPTIWSFLTKFL 348 (XXA, frog)

APOO826 Ref, Temporin-1Gd FILPLIASFLSKFL 349 (XXA, frog)

APOO827 Ref, Ranatuerin-1Ga SMISVLKNLGKVGLGFWACKVNKOC 350 (frog)

APOO829 Ref, Ranalexin-1G FLGGLMKIIPAAFCAWTKKC 351 (frog)

APOO830 Ref, Ranatuerin-2G GLILDTLKGAAKDIAGIALEKLKCKIT 352 (frog) GCKP

APOO831 Ref, Odorranain-NR GLISGILGAGKHIWCGLTGCAKA 353 (frog)

APOO832 Ref, Maximin H1 ILGPWISTIGGWLGGLLKNL 3.54 (XXA, toad)

APOO834 Ref. G. mellonella KWNANAIKKGGKAIGKGFKWISAAST 355 moricin-like peptide A AHDWYEHIKNRRH (Gm-mlpA, insect)

APOO835 Ref. G. mellonella GKIPVKAIKKGGOIIGKALRGINIASTA 356 moricin-like peptide B HDIISOFKPKKKKNH (Gm-mlpB, insect)

APOO836 Ref. G. mellonella KWPIGAIKKGGKIIKKGLGWIGAAGTA 357 moricin-like peptide C1 HEWYSHWKNRH (Gm-mlp C1, insect)

APOO837 Ref. G. mellonella KWPIGAIKKGGKIIKKGLGWLGAAGTA 358 moricin-like peptide C2 HEWYNHVRNRO (Gm-mlp C2, insect)

APOO838 Ref. G. mellonella KWPIGAIKKGGKIIKKGLGWIGAAGTA 359 moricin-like peptide C3 HEVYSHVKNRO (Gm-mlp C3, insect) US 8,389,679 B2 155 156 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial eptide database (aps. unmc.edu/APA main. hp).

SEQ ID Effector Structure/Sequence

APOO839 Ref. G. mellonella KWPWGAIKKGGKAIKTGLGWWGAAGT 1360 moricin-like peptide AHEWYSHIRNRH C4/C5 (Gm-mlpC4/C5, insect)

APOO84 O Ref. G. mellonella KGIGSALKKGGKIIKGGIGAL.GAIGTG 1361 moricin-like peptide D QQVYEHVONRQ (Gm-mlpD, insect)

APOO841 Ref, Enterocin A (EntA TTHSGKYYGNGVYCTKNKCTVDWAK 1362 class IIA bacteriocin, ATTCIAGMSIGGFLGGAIPGKC i.e. pediocin-like peptide, bacteria)

APOO842 Ref, Divercin W41 1363 (DVnV41, class IIa bacteriocin, pediocin like peptide, bacteria. DwnRV41 is the recombinant form)

APOO843 Ref, Divergic in M35 1364 (class IIa bacteriocin, pediocin-like peptide, bacteria)

APOO844 Ref, Coagulin KYYGNGWTCGKHSCSWDWGKATTCII 1365 (bacteriocin, pediocin NNGAMAWATGGHOGTHKC like peptide, bacteria)

APOO845 Ref, Listeriocin 743A KSYGNGWHCNKKKCWWDWGSAISTI 1366 (class IIa bacteriocin, GNNSAANWATGGAAGWKS pediocin-like peptide, bacteria)

APOO846 Ref, Mundticin KS KYYGNGWSCNKKGCSWDWGKAIGIIG 1367 (enterocin CRL35, NNSAANLATGGAAGWKS munditicin ATO6 mundticin QU2, class IIa bacteriocin, pediocin-like peptide, bacteria)

APOO847 Ref, Sakacin 5X KYYGNGLSCNKSGCSWDWSKAISIIGN 1368 (Sak5X class IIa NAVANLTTGGAAGWKS bacteriocin, pediocin like peptide, bacteria)

APOO848 Ref, Leucocin C (class KNYGNGWHCTKKGCSWDWGYAWAN 1369 IIa bacteriocin, IANNSWMNGLTGGNAGWHN pediocin-like peptide, bacteria)

APOO849 Ref, Lactococcin TSYGNGWHCNKSKCWIDWSELETYKA 1370 MMFII (class IIa GTWSNPKDILW. bacteriocin, pediocin like peptide, bacteria)

APOO850 Ref, Sakacin G (SakC, KYYGNGVSCNSHGCSVNWGOAWTC 1371. class IIa bacteriocin, GWNHLANGGHGVC pediocin-like peptide, bacteria)

APOO851 Ref, Plantaricin 423 KYYGNGVTCGKHSCSVNWGOAFSCS 1372 (class IIa bacteriocin, WSHLANFGHGKC pediocin-like peptide, bacteria)

APOO852 Ref, Plantaricin C19 KYYGNGLSCSKKGCTWNWGOAFSCG 1373 (class IIa bacteriocin, WNRWATAGHHKC pediocin-like peptide, bacteria) US 8,389,679 B2 157 158 TABL E 10 - continued Other illustrative antimicrobial peptides. AP numbers refer to ID in antimicrobial peptide database (aps. unmc.edu/APA main.

SEQ ID Effector Structure/Sequence APOO853 Ref, Enterocin P (EntP, ATRSYGNGWYCNNSKCWWNWGEAK 1374 class IIa bacteriocin, ENIAGIWISGWASGLAGMGH pediocin-like peptide, bacteria)

APOO854 Ref, Bacteriocin 31 ATYYGNGLYCNKOKCWVDWNKASR 1375 (Bac 31, Bac31, class EIGKIIVNGWVOHGPWAPR IIa bacteriocin, pediocin-like peptide, bacteria)

APOO855 Ref MSI-78 (XXA, 376 synthetic)

APOO856 Ref MSI-594 (XXA, GIGKFLKKAKKGIGAWLKWITTGL 377 synthetic)

APOO857 Ref, Catestatin (human SSMKLSFRARAYGFRGPGPOL 378 CHGA (352-372) , human Cist)

APOO 858 Ref, Temporin D (XXA, LPIWGNLLNSLL 379 frog)

APOO859 Ref, Temporin H (XXA, SPNLLKSLL 38O frog)

APOO 861 Ref, Brewinin-ALb PLAWSLAANFLPKLFCKITKKC 381 (frog)

APOO862 Ref, Brevin in 1E (frog) PLLAGLAANFLPKIFCKITKRC 382

APOO863 Ref, Temporin-ALla PIWGKLLSGLSGLL 383 (XXA, frog)

APOO 864 Ref, Temporin 1ARa PIWGRLISGLL 384 (XXA, frog)

APOO865 Ref, Temporin 1AUa LPIIGQLLSGLL 385 (XXA, Temporin 1AUa) (frog)

APOO866 Ref, Temporin 1Bya PIIAKWLSGLL 386 (XXA, Temporin-1Bya, frog)

APOO867 Ref, Temporin 1Ec PWIAGLISKL 387 (XXA, frog)

APOO 869 Ref, Temporin 1Ja ILPLWGNLLNDLL 388 (XXA, Temporin-1.Ja, frog)

APOO873 Ref, Temporin 1Pra ILPILGNLLNGLL 389 (XXA, frog)

APOO874 Ref, Temporin 1WE PLWGKILSGLI 390 (XXA, frog)

APOO875 Ref, Temporin 1Va SSIGKILGNLL 391 (XXA, frog)

APOO 876 Ref, Temporin 1Vb SIIAKWLGSLF 392 (XXA, frog)

APOO877 Ref, Brevinin-1.Ja (frog) LGSLIGAAIPAIKOLLGLKK 393

APOO 878 Ref, Brewinin-1BYa PILASLAAKFGPKLFCLWTKKC 394 (frog)

APOO884 Ref, Ixos in-B (tick) QLKVDLWGTRSGIOPEOHSSGKSDWR 395 RWRSRY