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Mechanism of action of, and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571

Leeds, Jennifer and Sachdeva, Meena and Mullin, Steve and Dzink-Fox, Joann and Lamarche, Matthew (2012) Mechanism of action of, and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571. Antimicrobial Agents and Chemotherapy, 56 (8). pp. 4463-4465. ISSN 0066-4804

Abstract

LFF571 is a novel semi-synthetic analog of the thiopeptide natural product GE2270 A and a potent inhibitor of Gram-positive aerobic and anaerobic bacteria. The parent compound is a translational inhibitor that binds elongation factor Tu (EF-Tu) and blocks its function. Here we report an analogous mechanism of action for LFF571 against Clostridium difficile. In exponentially growing cultures, LFF571 inhibited protein synthesis with an IC50 of 0.06 µg/ml. We also determined the frequency and mechanism of reduced susceptibility to the compound in vitro. Single-step, spontaneous mutants of C. difficile were selected on super-inhibitory concentrations of LFF571 at a frequency of <4.5 x 10-11 to 1.2 x 10-9. No C. difficile mutants with loss of LFF571 susceptibility emerged over ten serial passages in vitro. Sequence analysis of strains with reduced susceptibility to LFF571 revealed a single nucleotide substitution (g782a) in tufB or in tufA and tufB, resulting in a G260E change in the thiopeptide binding pocket of EF-Tu. This mutation did not confer cross-resistance to the clinically-used antimicrobials vancomycin or metronidazole, nor to the newly approved drug fidaxomicin. These results support the development of LFF571 as a treatment for C. difficile infection.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6414

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