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(12) Patent Application Publication (10) Pub. No.: US 2010/0322903A1 Collins Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0322903A1 Collins Et Al US 20100322903A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0322903A1 Collins et al. (43) Pub. Date: Dec. 23, 2010 (54) ENGINEERED BACTERIOPHAGES AS Related U.S. Application Data ADUVANTS FOR ANTIMICROBAL AGENTS AND COMPOSITIONS AND METHODS OF (60) Provisional application No. 61/020,197, filed on Jan. USE THEREOF 10, 2008. Publication Classification (75) Inventors: James J Collins, Newton, MA (US); Timothy Kuan-Ta Lu, (51) Int. Cl. Boston, MA (US) A6II 35/76 (2006.01) CI2N 7/01 (2006.01) Correspondence Address: A6IP3L/04 (2006.01) RONALDI. EISENSTEIN (52) U.S. Cl. ..................................... 424/93.2:435/235.1 100 SUMMER STREET, NIXON PEABODY LLP (57) ABSTRACT BOSTON, MA 02110 (US) The present invention relates to the treatment and prevention (73) Assignees: TRUSTEES OF BOSTON of bacteria and bacterial infections. In particular, the present UNIVERSITY, Boston, MA (US); invention relates to engineered bacteriophages used in com MASSACHUSETTS INSTITUTE bination with antimicrobial agents to potentiate the antimi OF TECHNOLOGY, Cambridge, crobial effect and bacterial killing by the antimicrobial agent. MA (US) The present invention generally relates to methods and com positions comprising engineered bacteriophages and antimi (21) Appl. No.: 12/812,212 crobial agents for the treatment of bacteria, and more particu larly to bacteriophages comprising agents that inhibit (22) PCT Filed: Jan. 12, 2009 antibiotic resistance genes and/or cell Survival genes, and/or bacteriophages comprising repressors of SOS response genes (86). PCT No.: PCT/USO9/30755 or inhibitors of antimicrobial defense genes and/or express ing an agent which increases the sensitivity of bacteria to an S371 (c)(1), antimicrobial agent in combination with at least one antimi (2), (4) Date: Aug. 31, 2010 crobial agent, and their use thereof. Patent Application Publication Dec. 23, 2010 Sheet 1 of 28 US 2010/0322903A1 VI‘9IJI X.X. Patent Application Publication Dec. 23, 2010 Sheet 2 of 28 US 2010/0322903A1 mmy--DItrºn-o– OI’0IJI 8II‘50IJI (Tu/n}))'soIV) 9NITTINNVAW Patent Application Publication Dec. 23, 2010 Sheet 3 of 28 US 2010/0322903A1 Y So (u/n}))'ioIV) 9NITTINNYaw g Y So (w/n)'SoIV) 9NITTINNYaw Patent Application Publication Dec. 23, 2010 Sheet 4 of 28 US 2010/0322903A1 y s v c- c. co St Lt Cd r of Patent Application Publication Dec. 23, 2010 Sheet 5 of 28 US 2010/0322903A1 INTRAPERITONEAL E. COI eZ NOTREATMENT NOPHAGE--OFLOX 1h POST-INFECTION (Pulian-OFLOX RECORD DALY SURVIVAL VTREATMENT WITH: UNMOD (Pleast OFLOX -O-NOTREATMENT -0-NOPHAGE--OFLOX 1OO -O-Pleast OFLOX 60 40 TREATMENT TIME (d) FIG. 3B Patent Application Publication Dec. 23, 2010 Sheet 6 of 28 US 2010/0322903A1 (O) STOINISISTIOI ENON Tul/?u08Ilu/ffu[)£.[]|:N|0}}(0THO| Patent Application Publication US 2010/0322903A1 W79™9IJI X.X, Patent Application Publication Dec. 23, 2010 Sheet 8 of 28 US 2010/0322903A1 (Cu/49)'BoIV) 9NITTINNYaw Patent Application Publication Dec. 23, 2010 Sheet 9 of 28 US 2010/0322903A1 X. X. X. X, *?JduI0$88WISO (O9°5)I,H. Patent Application Publication Dec. 23, 2010 Sheet 10 of 28 US 2010/0322903A1 tee O O -- s S s s e? Q) r R Patent Application Publication Dec. 23, 2010 Sheet 11 of 28 US 2010/0322903A1 819°5).I.H. Z (TW/40)'SoIV) SNITTINNVAW V9°50IJI Z (w/n)'50IV) 9NITTINNYaw Patent Application Publication Dec. 23, 2010 Sheet 12 of 28 US 2010/0322903A1 (19°5)I,H. s s (w/49)'SoIV) SNITTINNYaw 6}L9 ((|u/H8)"50DNOIIVINJONIHOVHA (O9(5)IZH (w/49)'SoIV) 9NITTINNYaw Patent Application Publication US 2010/0322903A1 ?VZNIOWNOTHOTUÂu0%+30||HdON (140)ST130INWISISIHTW10|| o o o s v o Patent Application Publication US 2010/0322903A1 SNOLAISO ONN O v [][][]|[][][]|-[][][]$[][][]|[][][]|-[][][]$[][]GZ[][][][Z[][][]|[][][]?[][][]| (140)ST130|N|S|S}\|T\||[]|([\{])STIHOIN?||S|SH8TW10|| CIZ,’9I,H(OZ.“OICH s SNOLVNasao OWN O s „—~~)^????????????????????????????????????????????N.„—~~~~)^?????????????????????????????????????????????N. Patent Application Publication Dec. 23, 2010 Sheet 15 of 28 US 2010/0322903A1 LP Co F op V8º9ICH LP CP r op Patent Application Publication Dec. 23, 2010 Sheet 16 of 28 US 2010/0322903A1 Patent Application Publication Dec. 23, 2010 Sheet 17 of 28 US 2010/0322903A1 s As do Patent Application Publication Dec. 23, 2010 Sheet 18 of 28 US 2010/0322903A1 Jduu0-- ?Jdu10-WISQ „H6°50IJI{{{6(5).I.H. Patent Application Publication Dec. 23, 2010 Sheet 19 of 28 US 2010/0322903A1 NIOWNOTHOTUÂuUZ £10I’0IJI INOOTO VOI"9IJI | INOOTO Patent Application Publication Dec. 23, 2010 Sheet 20 of 28 US 2010/0322903A1 CT0I’5)I,HI INOOTO NIJVYOIHOTUÂu09 (O0I’0IJI | INOOTO Patent Application Publication Dec. 23, 2010 Sheet 21 of 28 US 2010/0322903A1 {{0I’5)I,HI INOOTO Patent Application Publication Dec. 23, 2010 Sheet 22 of 28 US 2010/0322903A1 NOPHAGE M13mp18 M13mp 18-leXA3 2 -0.5 E S P 2 o 3S. -1 al H Se 2. s -1.5 FIG 11 Patent Application Publication Dec. 23, 2010 Sheet 24 of 28 US 2010/0322903A1 pZE1L-leXA E. AMPR CoE FIG. 13 Patent Application Publication Dec. 23, 2010 Sheet 25 of 28 US 2010/0322903A1 %. % % “%a %. 2, 2,2 E 4, 2.2 ' 22 22%. 0/2,2 %2 2 E 426, 222 % & SnE 22& o/2,2. 2% 2 42%. 222 & & 2 S2 % 2. 2. N as a 2% YN se % % % 2, 2. 3.2 Haza%2 “%% Q5N c5 %,2, 2 a.% R otst 22,%. 2 “ % .8- % 2. E 2,%. 2.2, % a % 2 % > % 2.% % H % 2,%. 22% TW/O 90T WITO 0/ Patent Application Publication Dec. 23, 2010 Sheet 26 of 28 US 2010/0322903A1 1 ---NOPHAGE 6 8 9 PHAGE INOCULATION (log(PFU/mL) FIG. 15 HAGE A. FIG. 16 Patent Application Publication Dec. 23, 2010 Sheet 27 of 28 US 2010/0322903A1 NOPHAGE 'union 'est 'ompF 'est-ompf FIG. 17 FIG. 18 Patent Application Publication Dec. 23, 2010 Sheet 28 of 28 US 2010/0322903A1 6I’9ICH US 2010/0322903A1 Dec. 23, 2010 ENGINEERED BACTERIOPHAGES AS co-infecting Enterococcus faecalis, which itself became ADUVANTS FOR ANTMICROBAL AGENTS completely resistant to Vancomycin in nosocomial settings by AND COMPOSITIONS AND METHODS OF 1988'''. Drugs such as ciprofloxacin that induce the SOS USE THEREOF response can even promote the horizontal dissemination of antibiotic resistance genes by mobilizing genetic elements' CROSS REFERENCE TO RELATED 16. For example, Streptococcus pneumoniae and Neisseria APPLICATIONS gonorrhoeae have also obtained resistance to antibiotics 0001. This application claims priority under 35 U.S.C. (Morens, et al., (2004) Nature 430: 242-249). Sub-inhibitory 119(e) of U.S. Provisional Patent Application Ser. No. concentrations or incomplete treatment courses can present 61/020,197 filed 10 Jan. 2008, the contents of which are evolutionary pressures for the development of antibiotic incorporated herein by reference in their entirety. resistance'7. Use of antibiotics outside of clinical settings, for example in livestockfor the agricultural industry, has contrib GOVERNMENT SUPPORT uted to the emergence of resistant organisms such as methi 0002 This invention was made with the Government Sup cillin-resistant staphylococci and is unlikely to abate due to port under Contract No. EF-0425719 awarded by the economic reasons and modern farming practices''. Resis National Science Foundation (NSF) and Contract No. tance genes that develop in non-clinical settings may be Sub OD003644 awarded by the National Institutes of Health sequently transmitted to bacterial populations which infect (NIH). The Government has certain rights in the invention. humans, worsening the antibiotic resistance problem'. 0007. In addition to acquiring antibiotic-resistance genes, FIELD OF THE INVENTION a small Subpopulation of cells known as persisters can Survive 0003. The present invention relates to the field of treat antibiotic treatment by entering a metabolically-dormant ment and prevention of bacteria and bacterial infections. In state'''. Persister cells do not typically carry genetic muta particular, the present invention relates to engineered bacte tions but rather exhibit phenotypic resistance to antibiotics'. riophages used in combination with antimicrobial agents to In Escherichia coli, the fraction of a population which repre potentiate the antimicrobial effect and bacterial killing of the sents persister cells increases dramatically in late-exponential antimicrobial agent. and stationary phases. Chromosomally-encoded toxins may be important contributors to the persister phenotype but the BACKGROUND underlying mechanisms that control the stochastic persis 0004 Bacteria rapidly develop resistance to antibiotic tence phenomena are not well understood’. Persisters drugs within years of first clinical use". Antibiotic resistance constitute a reservoir of latent cells that can begin to regrow can be acquired by horizontal gene transfer or result from once antibiotic treatment ceases and may be responsible for persistence, in which a small fraction of cells in a population the increased antibiotic tolerance observed in bacterial bio exhibits a non-inherited tolerance to antimicrobials. Since films'. By surviving treatment, persisters may play an antimicrobial drug discovery is increasingly lagging behind important role in the development of mutations or acquisition the evolution of antibiotic resistance, there is a pressing need of genes that confer antibiotic resistance. for new antibacterial therapies. 0008. Several strategies have been proposed for control 0005 Bacterial infections are responsible for significant ling antibiotic resistant infections. New classes of antibiotics morbidity and mortality in clinical settings. Though the would improve the arsenal of drugs available to fight antibi advent of antibiotics has reduced the impact of bacterial dis otic-resistant bacteria but few are in pharmaceutical pipe eases on human health, the constant evolution of antibiotic lines. Surveillance and containment measures have been resistance poses a serious challenge to the usefulness of instituted in government and hospitals so that problematic today’s antibiotic drugs'. Infections that would have been infections are rapidly detected and isolated but do not address easily cured by antibiotics in the past are now able to survive the fundamental evolution of resistance'.
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