MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridium difficile

Antimicrobial Agents and Chemotherapy

Volumn 56, Issue 9, 2012, Pages 4786-4792

  Butler, Michelle M ^a   Shinabarger, Dean L ^b   Citron, Diane M ^c   Kelly, Ciarán P ^d   Dvoskin, Sofya ^e   Wright, George E ^e   Feng, Hanping ^f,g   Tzipori, Saul ^f   Bowlin, Terry L ^a  

^a MICROBIOTIX INC   (United States)

^b Micromyx LLC   (United States)

^c R M ALDEN RESEARCH LABORATORY   (United States)

^d BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^e GLSYNTHESIS INC   (United States)

^f TUFTS UNIVERSITY   (United States)

^g UNIVERSITY OF MARYLAND   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; CLINDAMYCIN; CLINDAMYCIN PHOSPHATE; COLISTIN; GENTAMICIN; KANAMYCIN; MBX 500; METRONIDAZOLE; UNCLASSIFIED DRUG; VANCOMYCIN;

ANAEROBE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIUM ISOLATE; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM DIFFICILE INFECTION; CONTROLLED STUDY; DISEASE SEVERITY; DRUG APPROVAL; DRUG EFFICACY; DRUG POTENCY; HAMSTER; IN VITRO STUDY; IN VIVO STUDY; INFECTION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; RECURRENT DISEASE; RECURRENT INFECTION; WEIGHT GAIN;

ANIMALS; ANTI-BACTERIAL AGENTS; BACTERIAL PROTEINS; CLOSTRIDIUM DIFFICILE; CRICETINAE; DNA GYRASE; DNA TOPOISOMERASES, TYPE I; DNA-DIRECTED DNA POLYMERASE; ENTEROCOLITIS, PSEUDOMEMBRANOUS; ENZYME INHIBITORS; METRONIDAZOLE; MICE; SPECIES SPECIFICITY; SURVIVAL RATE; VANCOMYCIN; WEIGHT GAIN;

EID: 84865404667     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00508-12     Document Type: Article

References (32)

1. Aas J, Gessert CE, Bakken JS. 2003. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin. Infect. Dis. 36:580-585. (Pubitemid 36259562)
2. Allen SD, Emery CL, Siders JA. 1999. Clostridium, p 654-671. In Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH (ed), Manual of clinical microbiology, 7th ed. ASM Press, Washington, DC.
3. Anton PM, et al. 2004. Rifalazil treats and prevents relapse of Clostridium difficile-associated diarrhea in hamsters. Antimicrob. Agents Chemother. 48:3975-3979. (Pubitemid 39304630)
4. Bartlett JG. 2006. New drugs for Clostridium difficile infection. Clin. Infect. Dis. 43:428-431. (Pubitemid 44157149)
5. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. 1978. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N. Engl. J. Med. 298:531-534. (Pubitemid 8295586)
6. Bartlett JG, Perl TM. 2005. The new Clostridium difficile - what does it mean? N. Engl. J. Med. 353:2503-2505. (Pubitemid 41770171)
7. Bryskier A. 1997. Dual beta-lactam-fluoroquinolone compounds: a novel approach to antibacterial treatment. Expert Opin. Invest. Drugs 6:1479-1499. (Pubitemid 27432486)
8. Butler MM, et al. 2007. Antibacterial activity and mechanism of action of a novel anilinouracil-fluoroquinolone hybrid compound. Antimicrob. Agents Chemother. 51:119-127. (Pubitemid 46047696)
9. CDC. 2010. Fluoroquinolone resistance and Clostridium difficile, Germany. CDC, Atlanta, GA. http://wwwnc.cdc.gov/eid/article/16/4/09-0859-article.htm.
10. Chen X, et al. 2008. A mouse model of Clostridium difficile-associated disease. Gastroenterology 135:1984-1992.
11. CLSI. 2007. Methods for antimicrobial susceptibility testing of anaerobic bacteria; approved standard M11-A7. Clinical and Laboratory Standards Institute, Wayne, PA.
12. Geric B, et al. 2006. Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J. Infect. Dis. 193:1143-1150.
13. Hardesty JS, Juang P. 2011. Fidaxomicin: a macrocyclic antibiotic for the treatment of Clostridium difficile infection. Pharmacotherapy 31:877-886.
14. Hubschwerlen C, et al. 2003. Structure-activity relationship in the oxazolidinone-quinolone hybrid series: influence of the central spacer on the antibacterial activity and the mode of action. Bioorg. Med. Chem. Lett. 13:4229-4233. (Pubitemid 37410318)
15. Kelly CP, LaMont JT. 2008. Clostridium difficile - more difficult than ever. N. Engl. J. Med. 359:1932-1940.
16. Kokkotou E, et al. 2008. Comparative efficacies of rifaximin and vancomycin for treatment of Clostridium difficile-associated diarrhea and prevention of disease recurrence in hamsters. Antimicrob. Agents Chemother. 52:1121-1126. (Pubitemid 351358396)
17. Koo HL, Garey KW, Dupont HL. 2010. Future novel therapeutic agents for Clostridium difficile infection. Expert Opin. Invest. Drugs 19:825-836.
18. Lancaster JW, Matthews SJ. 2012. Fidaxomicin: the newest addition to the armamentarium against Clostridium difficile infections. Clin. Ther. 34:1-13.
19. McDonald LC, et al. 2005. An epidemic, toxin gene-variant strain of Clostridium difficile. N. Engl. J. Med. 353:2433-2441. (Pubitemid 41770164)
20. McFarland LV, Elmer GW, Surawicz CM. 2002. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am. J. Gastroenterol. 97:1769-1775. (Pubitemid 34761404)
21. Noren T, et al. 2006. Frequent emergence of resistance in Clostridium difficile during treatment of C. difficile-associated diarrhea with fusidic acid. Antimicrob. Agents Chemother. 50:3028-3032. (Pubitemid 44396408)
22. Pelaez T, et al. 2002. Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin. Antimicrob. Agents Chemother. 46:1647-1650. (Pubitemid 34535177)
23. Pelaez T, et al. 2008. Metronidazole resistance in Clostridium difficile is heterogeneous. J. Clin. Microbiol. 46:3028-3032.
24. Robertson GT, et al. 2008. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus. Antimicrob. Agents Chemother. 52:2313-2323. (Pubitemid 351915658)
25. Seal D, et al. 1987. Treatment of relapsing Clostridium difficile diarrhoea by administration of a nontoxigenic strain. Eur. J. Clin. Microbiol. 6:51-53. (Pubitemid 17034620)
26. Segarra-Newnham M. 2007. Probiotics for Clostridium difficile-associated diarrhea: focus on Lactobacillus rhamnosus GG and Saccharomyces boulardii. Ann. Pharmacother. 41:1212-1221. (Pubitemid 47122558)
27. Sougioultzis S, et al. 2005. Clostridium difficile toxoid vaccine in recurrent C. difficile-associated diarrhea. Gastroenterology 128:764-770. (Pubitemid 40585378)
28. Sun X, et al. 2011. Mouse relapse model of Clostridium difficile infection. Infect. Immun. 79:2856-2864.
29. Wilcox MH, Fawley WN, Settle CD, Davidson A. 1998. Recurrence of symptoms in Clostridium difficile infection - relapse or reinfection? J. Hosp. Infect. 38:93-100. (Pubitemid 28143351)
30. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. 2007. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin. Infect. Dis. 45:302-307. (Pubitemid 47101025)
31. Zhi C, et al. 2005. Synthesis and antibacterial activity of 3-substituted-6-(3-ethyl-4-methylanilino)uracils. J. Med. Chem. 48:7063-7074.
32. Zhi C, et al. 2006. Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors. J. Med. Chem. 49:1455-1465. (Pubitemid 43271899)