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Wo 2007/095187 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 23 August 2007 (23.08.2007) PCT WO 2007/095187 A2 (51) International Patent Classification: Not classified 29, D-85630 Grasbrunn (DE). THORMANN, Michael [DE/DE]; Kopernikusweg 1, D-82152 Martinsried (DE). (21) International Application Number: TREML, Andreas [DE/DE]; Bermeister Stolzl Str. 11, PCT/US2007/003698 94249 Bodenmais (DE). (22) International Filing Date: (74) Agent: JARRELL, Brenda, Herschbach; Choate, Hall & 13 February 2007 (13.02.2007) Stewart, Two International Place, Boston, MA 021 10 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (30) Priority Data: GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, 60/772,648 13 February 2006 (13.02.2006) US JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, 60/835,596 4 August 2006 (04.08.2006) US LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (71) Applicants (for all designated States except US): RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TRUSTEES OF BOSTON UNIVERSITY [US/US]; TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW One Sherborn Street, Boston, MA 02215 (US). CEL- LICON BIOTECHNOLOGIES, INC. [US/US]; 29 (84) Designated States (unless otherwise indicated, for every Linden Square, Wellesley, MA 02482 (US). PURETECH kind of regional protection available): ARIPO (BW, GH, VENTURES [US/US]; 222 Berkeley Street, Suite 1040, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Boston, MA 02116 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (75) Inventors/Applicants (for US only): COTTAREL, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, Guillaume [FR/US]; 4 Freeman Circle, Lexington, MA GN, GQ, GW, ML, MR, NE, SN, TD, TG). 02421 (US). WIERZBOWSKI, Jamey [US/US]; 35 Katherine Road, Stoneham, MA 02180 (US). PAL, KoUoI Published: [US/US]; 205 Tudor Road, Needham, MA 02492 (US). — without international search report and to be republished KOHANSKI, Michael [US/US]; 15 N Beacon Street, upon receipt of that report Apt. 1002, Allston, MA 02134 (US). DWYER, Daniel [US/US]; 15 Rangeley Road, Watertown, MA 02472 For two-letter codes and other abbreviations, refer to the "G uid (US). COLLINS, James [US/US]; One Sherborn Street ance Notes on Codes and Abbreviations" appearing at the beg in (US). ALMSTETTER, Michael [DE/DE]; Winklerring ning of each regular issue of the PCT Gazette. (54) Title: COMPOSITIONS AND METHODS FOR ANTIBIOTIC POTENTIATION AND DRUG DISCOVERS (57) Abstract: The present invention provides methods for identifying target genes whose partial or complete functional inactiva- tion potentiates the activity of an antibiotic agent, e.g., a quinolone antibiotic. The invention further provides methods for identifying agents that modulate expression of target genes or that modulate activity of expression products of target genes. Agents identified according to various methods of the invention potentiate the activity of antibiotics such as quinolones, aminoglycosides, peptide an- tibiotics and β-lactams. Also provided are agents that suppress and/or retard resistance to antibiotics. The inventive methods provide potentiating agents and compositions comprising potentiating agents and antibiotics. Such agents and compositions can be used for inhibiting growth or survival of a microbial cell or of treating a subject suffering from or susceptible to a microbial infection. Compositions and Methods for Antibiotic Potentiation and Drug Discovery Related Applications [0001] The present application claims priority from U.S. Provisional Application No. 60/772,648 filed on February 13, 2006 and entitled "Compositions and Methods for Antibiotic Potentiation and Drug Discovery", and ftom U.S. Provisional Application No. 60/835,596 filed on August 4, 2006 and entitled "Rec A Inhibition". Each of the provisional applications is incorporated herein by reference in its entirety. Background of the Invention [0002] J1 emergence of resistance to antibacterial agents is a growing problem for human and animal health, and new drugs to treat infections due to microorganisms that display resistance to currently used antibiotics are urgently needed. Efforts to overcome the growing problem of resistance have included modification of known antibiotics, classical screening of new compound libraries and natural product libraries, and genomic efforts to identify novel targets to which no cross resistance with existing antibiotics would be anticipated. Even with this significant antibiotic discovery effort, only a few agents that represent new chemical classes of antibiotic agents have been approved by regulatory agencies in recent years. In addition, few antibiotics that are effective against bacterial that have developed resistance to currently used antibiotics are in clinical development. Furthermore, a number of potent antibiotic agents are too toxic for clinical use or have significant side effects that limit their therapeutic utility. [0003] Quinolones are one of the most widely used classes of antimicrobial agents worldwide and serve to exemplify the promise and the problems associated with antibiotic development and use. Their therapeutic indications in humans have evolved from urinary tract infections to infections of almost all body compartments. Various members of the class are also widely administered for veterinary purposes. [0004] Quinolones exert their antimicrobial effect by targeting bacterial type II topoisomerases, namely gyrase and topoisomerase IV, essential enzymes that catalyze breakage and rejoining of DNA strands during normal cell growth. Quinolones form a ternary complex between DNA and either gyrase or topoisomerase IV, thereby blocking DNA replication and leading to events such as double-stranded DNA breaks that are rapidly lethal to the cell. As a class, quinolones have a broad spectrum of activity against Gram positive and Gram negative species, including both aerobic and anaerobic microorganisms. Activity against Gram negative microorganisms often depends strongly upon activity against DNA gyrase, while topoisomerase IV is often the primary target of quinolones that display activity against Gram positive species. A number of therapeutically useful quinolones display activity towards both of these targets. [0005] Quinolones, like most other antibiotics, can have adverse effects with the potential to affect virtually every major system in the body. The most frequent side effects associated with fluoroquinolone use involve the GI tract, skin, and/or central nervous system (CNS). Fluoroquinolones can also cause hypersensitivity reactions. A mild transient increase in liver function is seen in 2-3 % of the patients who are treated with a fluoroquinolone, and severe liver toxicity is a rare side effect of quinolone use. Cardiac side effects such as prolongation of the QT interval, which may predispose to serious arrhythmias, is also a concern. [0006] The adverse effects of many potent quinolones has hindered efforts to develop them as therapeutic agents. Gemifloxacin, for example, has an enhanced affinity for its target relative to many other quinolones and displays potent activity against most Gram positive cocci, particularly against Streptomycespneumoniae. Gemifloxacin is 30 fold more active than ciprofloxacin against this pathogen. Unfortunately, the side effects of the compound were significant enough that the further development by the pharmaceutical company was terminated. [0007] n addition, the rapid development of resistance to a number of quinolones is a cause for alarm and has led to a number of treatment failures. The spread of resistance has motivated calls for the development of policies that would restrict unnecessary use of these agents. Resistance can develop in a variety of ways including mutations in the genes encoding either DNA gyrase or topoisomerase IV and overexpression of efflux pumps. [0008] Quinolones are only one example of antibiotic agents that exhibit side effects and/or to which resistance has been developed. Thus, there is clearly a need in the art both for new agents to combat microbial infection and for new approaches to antibiotic drug discovery. There is also a need in the art for new approaches to improving the safety profile of certain antibiotics. Summary of the Invention [0009] The present invention provides compositions and methods for potentiating the activity of antibiotic agents and for discovering new agents of use in treating bacterial infection. [0010] In one aspect, the invention provides a method of inhibiting growth or survival of a microbial cell comprising: (a) contacting the microbial cell with a antibiotic (e.g., an quinolone); and (b) contacting the cell with an agent that potentiates activity of the antibiotic. [0011] In another aspect the invention provides a method of treating a subject in need thereof comprising: administering an antibiotic to the subject in combination with an agent that potentiates activity of the antibiotic hi certain embodiments of either
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