USOO9675592B2 (12) United States Patent (10) Patent No.: US 9,675,592 B2 Daum et al. (45) Date of Patent: Jun. 13, 2017 (54) METHODS AND COMPOSITIONS FOR (52) U.S. Cl. BACTERIA INFECTIONS CPC .......... A61K 31/431 (2013.01); A61K 9/0019 (71) Applicants: THE UNIVERSITY OF CHICAGO, ( 2013.01);) A6IK3I/05 ((2013.01): ) Chicago, IL (US): THE BOARD OF (Continued) REGENTS OF THE UNIVERSITY (58) Field of Classification Search OF ILLINOIS, Urbana, IL (US) CPC ... A61K 3 1/519; A61K 31/427; A61K 31/428; A61K 31/446 (72) Inventors: Robert S. Daum, Chicago, IL (US); Continued Susan Boyle-Vavra, Chicago, IL (US); (Continued) Michael E. Johnson, Urbana, IL (US) (56) References Cited (73) Assignees: The University of Chicago, Chicago, U.S. PATENT DOCUMENTS IL (US); The Board of Regents of the University of Illinois, Urbana, IL (US) 5,776,919 A 7, 1998 Sukigara et al. ............. 514, 161 2010.0029597 A1 2/2010 Cottarel et al. ............... 514,154 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. WO WO 2012151474 11 2012 WO WO 2014O71198 5, 2014 (21) Appl. No.: 14/776,965 (22) PCT Filed: Mar. 14, 2014 OTHER PUBLICATIONS (86). PCT No.: PCT/US2014/029237 Berge, et al., J Pharmaceutical Sci. 66(1):1-19, 1977. S 371 (c)(1)C s (Continued) (2) Date: Sep. 15, 2015 Primary Examiner — Shengjun Wang (87) PCT Pub. No.: WO2014/144710 Storney Agent, or Firm — Norton Rose Fulbright PCT Pub. Date: Sep. 18, 2014 (57) ABSTRACT (65) Prior Publication Data Compositions and methods are provided for treating or US 2016/0120852 A1 May 5, 2016 inhibiting a bacterial infection involving at least one anti Related U.S. Application Data biotic and a compound that potentiates the antibiotic activity of the antibiotic. In certain embodiments the antibiotic is a (60) Provisional application No. 61/789,716, filed on Mar. beta lactam. In further embodiments, the antibiotic is oxa 15, 2013. cillin. In additional embodiments, the potentiating com pound is an inhibitor of VraSR operon expression. In specific (51) Int. Cl. embodiments, the bacterial infection involves an antibiotic A6 IK 3/44 3.08: resistant bacteria. A 6LX 3/59 2006.O1 (Continued) 20 Claims, 6 Drawing Sheets 0.5 (ciacin)2 4mg. 5 US 9,675,592 B2 Page 2 (51) Int. Cl. 31/519 (2013.01); A61K3I/5377 (2013.01); A6 IK3I/53 (2006.01) A61K 31/7036 (2013.01); A61K 45/06 A6 IK 3/425 (2006.01) (2013.01) A6 IK 3L/45 (2006.01) (58) Field of Classification Search A6 IK3I/05 (2006.01) USPC ......... 514/736, 342, 260.1, 262.1, 367, 371, A6 IK 3/43 (2006.01) 514/245, 394, 259.31, 403,364 A6 IK 3/43 (2006.01) See application file for complete search history. A6 IK 45/06 (2006.01) (56) References Cited A6 IK 9/00 (2006.01) A6 IK 3/46 (2006.01) A6 IK 3/42.45 (2006.01) OTHER PUBLICATIONS A6 IK 3/428 (2006.01) Boyle-Vavra, et al., Antimicrob Agents Chemother: 57(1):83-95, A6 IK 3/4439 (2006.01) 2013. A6 IK 3L/454 (2006.01) Boyle-Vavra, et al., FEMS Microbiol Lett. 262(2):163-171, 2006. A 6LX 3L/24709 (2006.01) EllisO, et al., el, Antimicro C, teis Cleppother:ES' SS: Z 2011 A6 IK 3/4725 (2006.01) Livak & Schmittgen, St. 25(4):402-408, 2001. A6 IK 3/496 (2006.01) Montgomery, et al., J Infect Dis. 198(4):561-570, 2008. A 6LX 3/5.377 (2006.01) Rohner et al. “Synergistic Effect of Quinolones and Oxacillin on A6 IK3I/7036 (2006.01) Methicillin-Resistant Staphylococcus Species' Antimicrobial (52) U.S. Cl. Agents and Chemotherapy, 33(12): 2037-2041, 1989. CPC .......... A61K 31/416 (2013.01); A61K 31/428 Yin, et al., Antimicrobial Agents Chemother: 50(1):336-343, 2006. International Search Report and Written Opinion issued in PCT/ (2013.01); A61K 31/4245 (2013.01); A61 K US2014/029237, mailed on Aug. 11, 2014. 31/4439 (2013.01); A61K 31/454 (2013.01); Extended European Search Report for EP 14764384.5, mailed Oct. A6 IK3I/4709 (2013.01); A61K 31/4725 12, 2016. (2013.01); A61 K3I/496 (2013.01); A61 K Reynolds et al., Tuberculosis 92 (2012) 72-83. U.S. Patent Jun. 13, 2017 Sheet 1 of 6 US 9,675,592 B2 ! ------------------- O O.5 1 2 3 4. 5 6 6 18 Oxacillin) mg/L. time (hours * Ill 1 Oxacillin2 3 4mg/L. 5 6 F.G. 1 A-1C U.S. Patent Jun. 13, 2017 Sheet 2 of 6 US 9,675,592 B2 A 5 | vasr VraSR wraSR active 20 inactive uncertain average 15 average 10 as re-- """ g 20 3. uninhibited ' 15 og average s - 2 SD aWeaCe g 10 5 5 - 2 SD O --------- -----------T- DDDD • F- s -Y N) () a cu C N CO CO - a -a - a -a -a -a -a -a -a -a N) N. N. N. N. N. d - a Nad co -na cu o N Co co o -a n) ca) a U. ODs bin number FIG. 2A-2B U.S. Patent Jun. 13, 2017 Sheet 3 of 6 US 9,675,592 B2 1 2 3 4 5 6 7 His-VraS-C VraS-C U.S. Patent Jun. 13, 2017 Sheet 4 of 6 US 9,675,592 B2 3OO 2 250 200 150 O 10 20 30 40 (F2645-0188 (uM) FIG. 4 U.S. Patent Jun. 13, 2017 Sheet 5 of 6 US 9,675,592 B2 U.S. Patent Jun. 13, 2017 Sheet 6 of 6 US 9,675,592 B2 Y a . 3 3 3. ful 3. O D.5 2 4 8 6. 32 f 3 2 4 B 16 32 F2645-0.188 F5882-3050 V 2 4. - 8 - 16 - 32 64 O 0,5 1 2 4 8 16 32 FO020-1560 F1813-0712 O 2 4 8 16 32 64 O 0.5 1 2 4 8 16 32 F2703-0396 O F2619-0556 O 2 0.25 4 0.5 8 1 16 32 64 Growth in MBC (3-log Min conc to broth after 24 hr reduction in E reduce Ox MIC CFU) by 32x FIG. 6 US 9,675,592 B2 1. 2 METHODS AND COMPOSITIONS FOR 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl, 2,6-difluo BACTERIA INFECTIONS rophenyl, 2-bromothiophen-5-yl, 2-chlorothiophen-5-yl, 2-naphthyl 2-phenoxyphenyl, 2-phenylduinolin-4-yl, 3-(2- CROSS-REFERENCE TO RELATED chlorophenyl)-5-methylisoxazol-4-yl, 3,4,5-trimethoxyphe APPLICATIONS nyl, 3,5-dichlorophenyl, 3,5-dimethoxyphenyl, 3-bro mophenyl, 3-chlorobenzobthiophen-2-yl, 3-chlorophenyl, This application is a national phase application under 35 3-fluorophenyl, 3-methoxyphenyl, 3-n-butoxyphenyl, U.S.C. 371 of International Application No. PCT/US2014/ 3-phenoxyphenyl, 3-tolyl, 3-trifluoromethylphenyl, 4-(2,6- 09237, filed on Mar. 14, 2014, which claims the benefit of dimethylmorpholinosulfonyl)phenyl, 4-(2-ethylpiperidin-1- priority of U.S. Provisional Patent Application No. 61/789, 10 ylsulfonyl)phenyl, 4-(2-methylpiperidin-1-ylsulfonyl)phe 716, filed on Mar. 15, 2013. The entire contents of each of nyl, 4-(2-phenylduinoline), 4-(3,4-dihydroisoquinolin-2 the above-referenced disclosures are specifically incorpo (1H)-ylsulfonyl)phenyl, 4-(3,4-(dihydroquinolin-1 (2H)- rated herein by reference without disclaimer. ylsulfonyl)phenyl, 4-(3,5-dimethylpiperidin-1-ylsulfonyl) phenyl, 4-(4,4-dimethyloxazolidin-3-ylsulfonyl)phenyl, BACKGROUND OF THE INVENTION 15 4-(morpholinosulfonyl)phenyl, 4-(N,N-diallylsulfamoyl) 1. Field of the Invention phenyl, 4-(N,N-diethylsulfamoyl)phenyl, 4-(N,N-diisobu The present invention relates generally to the field of tylsulfamoyl)phenyl, 4-(N,N-dimethylsulfamoyl)phenyl, medicine. More particularly, it concerns the use of chemical 4-(N-ethyl-N-benzylsulfamoyl)phenyl, 4-(N-ethyl-N-n-bu compounds that inhibit the VraSR operon and potentiate the tyl-sulfamoyl)phenyl, 4-(N-ethyl-N-phenylsulfamoyl)phe action of antibiotics. nyl, 4-(N-isopropyl-N-benzylsulfamoyl)phenyl 4-(N- 2. Description of Related Art methyl-N-benzylsulfamoyl)phenyl, 4-(N-methyl-N- Staphylococcus aureus is a well-adapted human parasite cyclohexylsulfamoyl)phenyl, 4-(N-methyl-N-n- that is both a commensal and an important pathogen. It is butylsulfamoyl)phenyl, 4-(N-methyl-N-phenylsulfamoyl) responsible for a wide variety of infectious diseases that 25 phenyl, 4-(piperidin-1-ylsulfonyl)phenyl, 4-(pyrrolidin-1- range from minor skin abscesses to severe infections and ylsulfonyl)phenyl, 4-benzoylphenyl, 4-benzylphenyl, toxinoses requiring hospitalization. Staphylococcus aureus 4-biphenyl, 4-chlorophenyl, 4-diphenyl, 4-ethoxyphenyl, strains resistant to nearly all beta-lactams, so-called methi 4-fluorophenyl, 4-phenoxyphenyl, 4-tert-butylphenyl, cillin-resistant Staphylococcus aureus (MRSA), are a lead 30 7-methoxybenzofuran-2-yl, benzodthiazol-2-yl, benzod ing cause of healthcare associated and, since the 1990s, thiazol-4-yl, benzodthiazol-6-yl, benzofuran-2-yl, diphe community-associated infection. An epidemic of MRSA nylmethyl, methyl-4-benzoate, phenyl, or thiophen-2-yl, and infections has enhanced the urgency to identify alternative R may be 1,2,3,4-tetrahydronaphthalen-6-yl, 2-(methyl antibacterial agents for Successful treatment. Unfortunately, thio)phenyl, 2,3-dihydro-1,4-dioxin-2-yl, 2,3-dihydrobenzo this need comes at a time when the industry-driven pipeline 35 b1,4-dioxin-2-yl, 2,3-dihydrobenzob 1,4-dioxin-6-yl, for antibacterial development has slowed. 2,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethyl phenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl 2.5- SUMMARY OF THE INVENTION dimethylphenyl, 2-bromothiophen-2-yl, 2-chlorophenyl, 2-chlorothiophen-2-yl, 2-chlorothiophen-5-yl, 2-furanyl, Methods and compositions are provided for inhibiting, 40 2-methoxyphenyl, 2-pyridinyl, 3-(methylthio)phenyl, 3,4,5- preventing, or treating a bacterial infection, particularly trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphe bacteria that rely on a VraSR operon for signal transduction.