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In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin

Leeds, Jennifer and Sachdeva, Meena and Mullin, Steve and Barnes, Whitney and Ruzin, Alexey (2013) In vitro selection, via serial passage, of Clostridium difficile mutants with reduced susceptibility to fidaxomicin or vancomycin. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453

Abstract

Objectives: Current treatments for Clostridium difficile infection include vancomycin, metronidazole, and fidaxomicin. LFF571 is an experimental agent undergoing evaluation in humans for the treatment of moderate C. difficile infection. Reduced susceptibility of C. difficile to fidaxomicin or LFF571 in vitro can be mediated by single point mutations in the genes encoding the targets, whereas the mechanism(s) mediating reduced susceptibility to vancomycin in vitro remains elusive. To further characterize mechanisms reducing susceptibility of C. difficile to vancomycin, fidaxomicin, or LFF571 in vitro selections via serial passage at low cell density and whole genome sequencing were performed.
Methods: C. difficile strains ATCC43255 and three clinical isolates were subjected to 10 passages on medium containing a range of concentrations of fidaxomicin, LFF571 or vancomycin. Genomic DNA from isolates with reduced susceptibility was sequenced using Illumina Whole Genome Sequencing.
Results: Clones exhibiting decreased susceptibility to fidaxomicin harbored mutations in rpoB and CD22120 (marR homolog). Clones exhibiting decreased susceptibility to vancomycin harbored mutations in rpoC and also in CD2725, CD3659 and sdaB which encode putative N-acetylglucosamine transferase, exonuclease and L-serine deaminase, respectively. All mutations resulted in nonsynonymous substitutions in the encoded proteins. No clones with reduced susceptibility to LFF571 were selected in this study.
Conclusions: Reduced susceptibility to fidaxomicin and vancomycin was associated with mutations mediating target modifications (RNA polymerase or cell wall, respectively), as well as with mutations that may contribute to reduced susceptibility via other mechanisms. The MIC of LFF571 was unaffected in those mutants with reduced susceptibility to fidaxomicin or vancomycin.

Item Type: Article
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Additional Information: Information in this manuscript is identical to that which was approved, in OAK, for disclosure at ICAAC last year.
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9912

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