Sachdeva, Meena and Leeds, Jennifer (2015) Sub-inhibitory concentrations of LFF571 reduce toxin production by Clostridium difficile. Antimicrobial Agents and Chemotherapy, 59 (2). pp. 1252-1257. ISSN 1098-6596

Abstract

LFF571 is a novel semi-synthetic thiopeptide antibacterial that is undergoing investigation for safety and efficacy in patients with moderate C. difficile infections. LFF571 inhibits bacterial protein synthesis by interacting with elongation factor Tu (EF-Tu) and interrupting complex formation between EF-Tu and aminoacyl-tRNA. Given this mechanism of action, we hypothesized that concentrations of LFF571 below those necessary to inhibit bacterial growth would reduce steady state toxin levels in C. difficile cultures. We investigated C. difficile growth and toxin A/B levels in the presence of LFF571, fidaxomicin, vancomycin and metronidazole. LFF571 led to strain-dependent effects on toxin production, including decreased toxin levels after treatment with sub-inhibitory concentrations, and more rapid declines in toxin production compared to inhibition of colony formation. Fidaxomicin, which is an RNA synthesis inhibitor, conferred a similar pattern to LFF571 with respect to toxin levels versus viable cell counts. Incubation of two toxigenic C. difficile strains with sub-inhibitory concentrations of vancomycin, a cell wall synthesis inhibitor, increased toxin levels in the supernatant compared to untreated cultures. A similar phenomenon was observed with one metronidazole-treated strain of C. difficile. These studies indicate that LFF571 and fidaxomicin generally result in decreased C. difficile toxin levels in culture supernatants, whereas treatment of some strains with vancomycin or metronidazole had the potential to increase toxin levels. Although the relevance of these findings remains to be studied in patients, reducing toxin levels with sub growth-inhibitory concentrations of antibiotic is hypothesized to be beneficial in alleviating symptoms.

Item Type:	Article
Date Deposited:	29 Apr 2016 23:45
Last Modified:	29 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/21074