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(12) Patent Application Publication (10) Pub. No.: US 2009/0264342 A1 Cottarel Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0264342 A1 Cottarel Et Al US 20090264.342A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0264342 A1 Cottarel et al. (43) Pub. Date: Oct. 22, 2009 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data ANTIBOTC POTENTATION AND DRUG (60) Provisional application No. 60/772,648, filed on Feb. DISCOVERY 13, 2006, provisional application No. 60/835,596, (75) Inventors: Guillaume Cottarel, Mountain filed on Aug. 4, 2006. View, CA (US); Jamey Publication Classification Wierzbowski, Stoneham, MA (US); Kolol Pal, Needham, MA (US); (51) Int. Cl. Michael Kohanski, Allston, MA A638/00 (2006.01) (US); Daniel Dwyer, Watertown, CI2O I/68 (2006.01) MA (US); James Collins, Newton, CI2N 5/02 (2006.01) MA (US); Michael Almstetter, A63L/70 (2006.01) Grasbrunn (DE); Michael A63L/435 (2006.01) Thormann, Martinsried (DE); A63L/352 (2006.01) Andreas Treml, Bodenmais (DE) (52) U.S. Cl. ................... 514/9:435/6: 435/375; 514/42: 514/277; 514/456 Correspondence Address: (57) ABSTRACT CHOATE, HALL & STEWART LLP TWO INTERNATIONAL PLACE The present invention provides methods for identifying target BOSTON, MA 02110 (US) genes whose partial or complete functional inactivation potentiates the activity of an antibiotic agent, e.g., a quinolone (73) Assignees: TRUSTEES OF BOSTON antibiotic. The invention further provides methods for iden UNIVERSITY, Boston, MA (US); tifying agents that modulate expression of target genes or that PURETECH VENTURES, modulate activity of expression products of target genes. Boston, MA (US) Agents identified according to various methods of the inven tion potentiate the activity of antibiotics such as quinolones, (21) Appl. No.: 12/279,237 aminoglycosides, peptide antibiotics and B-lactams. Also provided are agents that suppress and/or retard resistance to (22) PCT Filed: Feb. 13, 2007 antibiotics. The inventive methods provide potentiating agents and compositions comprising potentiating agents and (86). PCT No.: PCT/US07/03698 antibiotics. Such agents and compositions can be used for inhibiting growth or survival of a microbial cellor of treating S371 (c)(1), a subject suffering from or susceptible to a microbial infec (2), (4) Date: May 21, 2009 tion. Patent Application Publication Oct. 22, 2009 Sheet 1 of 50 US 2009/0264.342 A1 Figure Patent Application Publication Oct. 22, 2009 Sheet 2 of 50 US 2009/0264.342 A1 ||nu?p?j Figure 2 Patent Application Publication Oct. 22, 2009 Sheet 3 of 50 US 2009/0264.342 A1 |ºp?JBI----- unulapºnaj--l?t ?SIS3) ens so Figure 3 Patent Application Publication Oct. 22, 2009 Sheet 4 of 50 US 2009/0264.342 A1 to exceN. Le AAins d N Figure 4 Patent Application Publication Oct. 22, 2009 Sheet 5 of 50 US 2009/0264.342 A1 ?ÅÅ---+---- [3]&#334----+---- Figure 5 Patent Application Publication Oct. 22, 2009 Sheet 6 of 50 US 2009/0264.342 A1 Figure 6 Patent Application Publication Oct. 22, 2009 Sheet 7 of 50 US 2009/0264.342 A1 d-No.:001dyw: | uluggg Asueui Figure 7 Patent Application Publication Oct. 22, 2009 Sheet 8 of 50 US 2009/0264.342 A1 ( E E (s BWWef-dy A. dwellp'W09 < . E O sis s Saul Figure 8 Patent Application Publication Oct. 22, 2009 Sheet 9 of 50 US 2009/0264.342 A1 O. : O alt O O S 4. 4. 13 O r is OH N12 7SNNN-2 3 8 4-oxo-4-dihydroquinoline 4-oxo-1,4-dihydronaphthyridine Figure 9 4-Quirolone 2-Pyridone O O O O S is OH 72°NN 3 OH 7 N12 BS1S-12 S 9 4-oxo-1,4-dihydroquinoline 4H-4-oxoquinoltzine O O S R. O f 5 s 7s 2 'on 2S1'sCroitN \, 18 4-oxo-1,4-dihydronaphthyridine 6H-6-oxo-pyrido1,2-apyiridise Figure 10 Patent Application Publication Oct. 22, 2009 Sheet 10 of 50 US 2009/0264.342 A1 benzobnaphthyidones O O F 21 21 O Me . R. Figure 11 (A) Patent Application Publication Oct. 22, 2009 Sheet 11 of 50 US 2009/0264.342 A1 y-df CC N y-/ O e-N R Diberizoi,5naphthyridiones ad C, OH HN R N OR F Rio 1-Hydroxy-7-amino-s-acidones Pyrrolo[1,2-aquinclinesO , and isDindolo2,1-aquinolines (7 NH A-B O O. N -d R AN R AN Pyi Toiloquinolones and Pyrazoloquinolones O O F CN, N- OH R 2-4-(4-Fluorophenyl)piperzin-1-yl)-4,7-dihydro-7-to-1,2,4-triaepio 5-epyrimidine-6- carboxylic Acids "" O R NS OH r1N1 R p-Quinone ethicies Figure 11 (B) Patent Application Publication Oct. 22, 2009 Sheet 12 of 50 US 2009/0264342 A1 +183INEGIT*annya3800s uopeajasu00ÁJønt) Odulo Odulo Odulo wasx yasx OÅ3003 01 EN35)G?1190?T Figure 12 (page 1 of 11) Patent Application Publication Oct. 22, 2009 Sheet 13 of 50 US 2009/0264.342 A1 9821476 98?,176 Figure 12 (page 2 of 11) Patent Application Publication Oct. 22, 2009 Sheet 14 of 50 US 2009/0264.342 A1 o co do o se c o co C C C Co o O C C Co o o o O O Co o Figure 12 (page 3 of 11) Patent Application Publication Oct. 22, 2009 Sheet 15 of 50 US 2009/0264.342 A1 gure 12 (page 4 of 11) Patent Application Publication Oct. 22, 2009 Sheet 16 of 50 US 2009/0264.342 A1 Figure 12 (page 5 of 11) Patent Application Publication Oct. 22, 2009 Sheet 17 of 50 US 2009/0264.342 A1 Figure 12 (page 6 of 11) Patent Application Publication Oct. 22, 2009 Sheet 18 of 50 US 2009/0264.342 A1 N001 Figure 12 (page 7 of 11) Patent Application Publication Oct. 22, 2009 Sheet 19 of 50 US 2009/0264.342 A1 Figure 12 (page 8 of 11) Patent Application Publication Oct. 22, 2009 Sheet 20 of 50 US 2009/0264342 A1 984. G8!. 8.199ff6 699&#78 698976 Figure 12 (page 9 of 11) Patent Application Publication Oct. 22, 2009 Sheet 21 of 50 US 2009/0264.342 A1 Figure 12 (page 10 of 11) Patent Application Publication Oct. 22, 2009 Sheet 22 of 50 US 2009/0264.342 A1 Figure 12 (page 11 of 11) Patent Application Publication Oct. 22, 2009 Sheet 24 of 50 US 2009/0264342 A1 Database Chemical Percent Structure D Name Inhibition ICso (ig/mL) CC lg/mL COC FO2 BO9 Armentoflavone 109 OO5 Aos SORHAMNETN 1 OO C C CO OC on IF Ot G05 NOKFAVONE 1001 AO 88 OOO FO2 B08 Maclurin 1 OO15 or CO P FO2 sco, EO7 heafavin 501-5 F02 A06 KAEMPFEROL 7O 1 OO15 Figure 14 (page 1 of 2) Patent Application Publication Oct. 22, 2009 Sheet 25 of 50 US 2009/0264.342 A1 Structure Database Chemical Percent -Cio- D Name Inhibition ug/nl. IC50 (ug/mL) CD 01 G08 Cuercetin dihydrate 67 2OO AO8 3,7,4'- RHYDROXYFLAV A ONE 63. DO10 CO3 6, 200100 E03 ic? AO3 QUERCETAGETIN 1 OO16 FD1- APIGENIN-7-O- AO2 GLUCOSDE 48 OO-1 Figure 14 (page 2 of 2) Patent Application Publication Oct. 22, 2009 Sheet 26 of 50 US 2009/0264.342 A1 Figure 15 Patent Application Publication Oct. 22, 2009 Sheet 27 of 50 US 2009/0264.342 A1 o. 3 3:0o "), h wae ; (3ossr"), Figure 16 (page 1 of 2) Patent Application Publication Oct. 22, 2009 Sheet 28 of 50 US 2009/0264.342 A1 gö, £ ºº. Taewaenyusw-gway!!!!!!?Turgs: Figure 16 (page 2 of 2) Patent Application Publication Oct. 22, 2009 Sheet 29 of 50 US 2009/0264.342 A1 2 s E 2 S ca k 2 3 2. 2 my aps g s 2. O All Sg . R i. o CO N CO l re To -- (Bujueue.) - 'w) adualsalun a Aleja. Figure 17 Patent Application Publication Oct. 22, 2009 Sheet 30 of 50 US 2009/0264342 A1 Figure 18 Patent Application Publication Oct. 22, 2009 Sheet 31 of 50 US 2009/0264.342 A1 OSWICI Figure 19 Patent Application Publication Oct. 22, 2009 Sheet 32 of 50 US 2009/0264.342 A1 Patent Application Publication Oct. 22, 2009 Sheet 33 of 50 US 2009/0264.342 A1 Figure 21 Patent Application Publication Oct. 22, 2009 Sheet 34 of 50 US 2009/0264.342 A1 Figure 22 Patent Application Publication Oct. 22, 2009 Sheet 35 of 50 US 2009/0264.342 A1 Figure 23 Patent Application Publication Oct. 22, 2009 Sheet 36 of 50 US 2009/0264.342 A1 g s C . C d D C 2 Patent Application Publication Oct. 22, 2009 Sheet 37 of 50 US 2009/0264.342 A1 spuen?nopeq03-11ps????s?ºñou??L, ?uauu!!?!!--uluO!!!SOd Figure 25 Patent Application Publication Oct. 22, 2009 Sheet 38 of 50 US 2009/0264.342 A1 Figure 26 Patent Application Publication Oct. 22, 2009 Sheet 39 of 50 US 2009/0264.342 A1 Figure 27 Patent Application Publication Oct. 22, 2009 Sheet 40 of 50 US 2009/0264.342 A1 \/09.,uun.I?oedspeoug ?jq?ssodslog?q??u? ???SMAÐN Figure 28 Patent Application Publication Oct. 22, 2009 Sheet 41 of 50 US 2009/0264342 A1 Gene O Description ace O114 ara 96 b3. atpH 837356T bO401 cydB b0734 cytochromed terminal oxidase polypeptide subunit degF DNA biosynthesis; primosomal protein i fepD b0590 ferric enterobactin (enterochein) transport guab TTE250B IMP dehydrogenase T scS b2530 putative aminotransferase JWS360 lipoamide dehydrogenase (NADH); component of 2-oxodehydrogenase and pyruvate complexes; L-protein of glycine cleavage complex nuoB 52287 NADH dehydrogenase chain B osme b1283 osmotically inducible lipoprotein priA 53935 primosomal protein NE factor Y(putative helicase) pris b420 prinosomal replication protein N recA DNA strand exchange and renaturation, DNA-dependent ATPase, DNA- and ATP dependent coprotease fad ADP---glycero-D-mannoheptose-6-epimerase rpm 53299 50S ribosoma subunit protein 36 T rpoo b3057 RNA polymerase, sigma(70) factor regulation of proteins induced at high ta seda boss negative modulator of initiation of replication TT setA .
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