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(12) United States Patent (10) Patent No.: US 9,056,899 B2 Collins Et Al US009056899B2 (12) United States Patent (10) Patent No.: US 9,056,899 B2 Collins et al. (45) Date of Patent: Jun. 16, 2015 (54) ENGINEERED BACTERIOPHAGES AS FOREIGN PATENT DOCUMENTS ADUVANTS FOR ANTIMICROBAL AGENTS AND COMPOSITIONS AND METHODS OF EP O112803 4f1984 USE THEREOF OTHER PUBLICATIONS (75) Inventors: James J Collins, Newton Center, MA Alekshun et al. Molecular mechanisms of antibacterial multidrug (US); Timothy Kuan-Ta Lu, Boston, resistance. Cell 128, 1037-1050 (2007). MA (US) Avery, S.V. Microbial cell individuality and the underlying sources of heterogeneity. Nat Rev Microbiol 4, 577-587 (2006). (73) Assignees: Trustees of Boston University, Boston, Balaban et al. Bacterial persistence as a phenotypic Switch. Science MA (US); Massachusetts Institute of 305, 1622-1625 (2004). Technology, Cambridge, MA (US) Beaber et al. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 427, 72-74 (2004). Bergstrom et al. Ecological theory Suggests that antimicrobial (*) Notice: Subject to any disclaimer, the term of this cycling will not reduce antimicrobial resistance in hospitals. Proc patent is extended or adjusted under 35 Natl AcadSci U S A 101, 13285-13290 (2004). U.S.C. 154(b) by 744 days. Bonhoeffer et al. Evaluating treatment protocols to prevent antibiotic resistance. Proc Natl AcadSci U S A94, 12106-12111 (1997). (21) Appl. No.: 12/812,212 Brown et al., Antibiotic cycling or rotation: a systematic review of the evidence of efficacy. Journal of Antimicrobial Chemotherapy, 55, 6-9 (22) PCT Filed: Jan. 12, 2009 (2005). Brissow, H. Phage therapy: the Escherichia coli experience. (86). PCT No.: PCT/US2009/030755 Microbiology 151, 2133-2140 (2005). S371 (c)(1), Chait et al. Antibiotic interactions that select against resistance. Nature 446, 668-671 (2007). (2), (4) Date: Aug. 31, 2010 Chang et al. Infection with Vancomycin-resistant Staphylococcus aureus containing the VanA resistance gene, NE Journal of Medicine (87) PCT Pub. No.: WO2009/108406 348, 1342-1347 (2003). PCT Pub. Date: Sep. 3, 2009 Curtin et al. Using Bacteriophages to reduce formation of catheter associated biofilms by Staphylococcus epidermis, (2006) (65) Prior Publication Data Antimicrob. Agents Chemother. 50; 1268-1275. Dwyer, D.J., Kohanski, M.A., Hayete, B. & Collins, J.J. Gyrase US 2010/0322903A1 Dec. 23, 2010 inhibitors induce an oxidative damage cellular death pathway in Escherichia coli. Mol Syst Biol 3, 91 (2007). From the Centers for Disease Control and Prevention. Four pediatric Related U.S. Application Data deaths from community-acquired methicillin-resistant Staphylococ cus aureus—Minnesota and North Dakota, 1997-1999. JAMA. (60) Provisional application No. 61/020,197, filed on Jan. Hagens et al. Genetically modified filamentous phage as bactericidal 10, 2008. agents: a pilot study. Lett. Appl. Microbiol. 37, 318-323 (2003). (51) Int. Cl. Hagens et al. Augmentation of the antimicrobial efficacy of antibiot AOIN 63/00 (2006.01) ics by filamentous phage. Microb Drug Resist 12, 164-168 (2006). CI2N 7/01 (2006.01) (Continued) C07K I4/005 (2006.01) A6 IK35/76 (2015.01) Primary Examiner — Michael Burkhart CI2N IS/II3 (2010.01) (74) Attorney, Agent, or Firm — Nixon Peabody, LLP (52) U.S. Cl. CPC ............... C07K 14/005 (2013.01); A61 K35/76 (57) ABSTRACT (2013.01); C12N 15/I 13 (2013.01); C12N The present invention relates to the treatment and prevention 2320/32 (2013.01); C12N 2330/30 (2013.01); of bacteria and bacterial infections. In particular, the present CI2N2795/14 122 (2013.01); C12N invention relates to engineered bacteriophages used in com 2795/14132 (2013.01) bination with antimicrobial agents to potentiate the antimi (58) Field of Classification Search crobial effect and bacterial killing by the antimicrobial agent. None The present invention generally relates to methods and com See application file for complete search history. positions comprising engineered bacteriophages and antimi crobial agents for the treatment of bacteria, and more particu (56) References Cited larly to bacteriophages comprising agents that inhibit U.S. PATENT DOCUMENTS antibiotic resistance genes and/or cell Survival genes, and/or bacteriophages comprising repressors of SOS response genes 4,559,078 A 12/1985 Maier or inhibitors of antimicrobial defense genes and/or express 4,677,217 A 6, 1987 Maier ing an agent which increases the sensitivity of bacteria to an 4,678,750 A 7/1987 Vandenbergh et al. 6,335,012 B1 1/2002 Fischetti et al. antimicrobial agent in combination with at least one antimi 6,699,701 B1 3, 2004 Sulakvelidze et al. crobial agent, and their use thereof. 2005, 000403.0 A1 1/2005 Fischetti et al. 2012/03.01433 A1* 11/2012 Lu et al. ....................... 424.93.2 20 Claims, 28 Drawing Sheets US 9,056,899 B2 Page 2 (56) References Cited Ubeda et al. Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in OTHER PUBLICATIONS staphylococci. Mol. Microbiol. 56, 836-844 (2005). Hagens et al. Therapy of experimental pseudomonas infections with Vandenesch et al. Community-acquired methicillin-resistant a nonreplicating genetically modified phage. Antimicrob. Agents Staphylococcus aureus carrying Panton-Valentine leukocidin genes: Chemother. 48, 3817-3822 (2004). worldwide emergence. Emerg. Infect. Dis. 9, 978-984 (2003). Hall, B.G. Predicting the evolution of antibiotic resistance genes. Nat Vázquez-Laslop et al. Increased persistence in Escherichia coli Rev Microbiol 2, 430-435 (2004). caused by controlled expression of toxins or other unrelated proteins. Hall-Stoodley et al. Bacterial biofilms: from the natural environment J. Bacteriol. 188, 3494-3497 (2006). to infectious diseases. Nat Rev Microbiol 2,95-108 (2004). Walsh, C. Where will new antibiotics come from? Nat Rev Microbiol Heitman et al. Phage Trojan horses: a conditional expression system 1, 65-70 (2003). for lethal genes. Gene 85, 193-197 (1989). Huff et al...Therapeutic Efficacy of Bacteriophage and Baytril Wang et al. Platensinycin is a selective FabF inhibitor with potent (Enrofloxacin) Individually and in Combination to Treat Colibacil antibiotic properties. Nature 441, 358-361 (2006). losis in Broilers, Poultry Science, 83, 1994-1947 (2004). Wise, R. The relentless rise of resistance? J. Antimicrob. Chemother. Klevens et al. Invasive methicillin-resistant Staphylococcus aureus 54, 306–310 (2004). infections in the United States. JAMA 298, 1763-1771 (2007). Wiuff et al. Phenotypic tolerance: antibiotic enrichment of Kohanski et al. A common mechanism of cellular death induced by noninherited resistance in bacterial populations. Antimicrob. Agents bactericidal antibiotics. Cell 130, 797-810 (2007). Chemother. 49, 1483-1494 (2005). Korch et al. 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Persister cells, dormancy and infectious disease. Nat Rev Kwon, NH et al., “Staphylococcal cassette chromosome mec Microbiol (2006). (SCCmec) characterization and molecular analysis for methicillin Loose et al. A linguistic model for the rational design of antimicrobial resistant Staphylococcus aureus and novel SCCmec Subtype IVg peptides. Nature 443, 867-869 (2006). isolated from bovine milk in Korea.” Journal of Antimicrobial Che Lorch, A. “Bacteriophages: An alternative to antibiotics?” motherapy 56:624-632, 2005. Biotechnology and Development Monitor, No. 39, pp. 14-17 (1999). Westwater, Cet al., “Use of Genetically Engineered Phage to Deliver Martinez et al. Mutation frequencies and antibiotic resistance. Antimicrobial Agents to Bacteria: an Alternative Therapy for Treat Antimicrob. Agents Chemother. 44, 1771-1777 (2000). ment of Bacterial Infections.” Antimicrobial Agents and Chemo Morens et al. The challenge of emerging and re-emerging infectious therapy 47(4): 1301-1307, 2003. diseases. Nature 430, 242-249 (2004). Lu, T Combating Biofilms and Antibiotic Resistance Using Synthetic Projan, S. Phage-inspired antibiotics? Nat. Biotechnol. 22, 167-168 Biology. DSPACE(aMIT, Dec. 11, 2008. (2004). Lu, TK "Curriculum Vitae.” Internet Article, pp. 1-8. Salyers et al. Human intestinal bacteria as reservoirs for antibiotic Yanisch-Perron C et al., “Improved M-13 Phage Cloning Vectors and resistance genes. Trends Microbiol. 12, 412-416 (2004). Host Strains Nucleotide Sequence of the M-13MP-18 and PUC-19 Schoolnik et al. Phage offer a real alternative. Nat. Biotechnol. 22. Vectors.” Database Biosis, Biosciences Information Service, Phila 505-507 (2004). delphia, PA. Database Accession No. PREV 198580021779, Gene Shah et al. Persisters: a distinct physiological state of E. coli. BMC
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