Inhibitory effect of REP3123 on toxin and spore formation in Clostridium difficile, and in vivo efficacy in a hamster gastrointestinal infection model

• Published in: Journal of antimicrobial chemotherapy 2009-05, Vol.63 (5), p.964-971
• Main Authors: Ochsner, Urs A., Bell, Stacie J., O'Leary, Ann L., Hoang, Teresa, Stone, Kimberley Clawson, Young, Casey L., Critchley, Ian A., Janjic, Nebojsa
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Toxins - biosynthesis; Benzopyrans - pharmacology; Biological and medical sciences; C. difficile infection; Cell Line; Clostridium difficile; Clostridium difficile - drug effects; Cricetinae; Enterocolitis, Pseudomembranous - drug therapy; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; hamster efficacy model; Infections; Inhibitor drugs; Male; Medical sciences; Pharmacology. Drug treatments; Ribonucleic acid; RNA; Rodents; Spores, Bacterial - drug effects; sporulation; Survival Analysis; Thiophenes - pharmacology; Vancomycin - pharmacology; Vancomycin - therapeutic use
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkp042

Objectives REP3123 is a fully synthetic methionyl-tRNA synthetase inhibitor in pre-clinical development as a novel agent to treat Clostridium difficile infection (CDI). This novel agent was investigated for its ability to block the production of toxins and spores, and was tested for efficacy in vivo in a hamster model. Methods Clostridial toxin levels were determined qualitatively using monoclonal antibodies and by cytotoxicity assays. Spores were detected by staining and by quantitative dilution plating after ethanol treatment. Efficacy of REP3123 was tested in a clindamycin-induced C. difficile hamster gastrointestinal (GI) infection model. Results REP3123 at concentrations as low as 1 mg/L inhibited de novo toxin production in high cell density, stationary phase cultures of C. difficile. Among comparator agents currently used for CDI therapy, vancomycin required much higher levels of 20 mg/L, and metronidazole had no effect on toxin levels. REP3123 caused a >10-fold reduction of the sporulation rate in vitro. Vancomycin and, in particular, metronidazole appeared to promote the formation of spores. REP3123, at concentrations as low as 0.5 mg/kg, demonstrated efficacy in the hamster model of CDI and was superior to vancomycin in the overall survival of the animals at the end of the study (33 days). Conclusions REP3123 inhibited growth of C. difficile, affected the production of toxins and spores and demonstrated superior efficacy compared with vancomycin in the hamster GI infection model. This agent may be a promising candidate for CDI treatment; in particular, the inhibition of toxin production and spore formation may reduce the severity and spread of the disease, respectively.