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(12) United States Patent (10) Patent No.: US 8,389,679 B2 Eckert Et Al

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(12) United States Patent (10) Patent No.: US 8,389,679 B2 Eckert Et Al 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 ..
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