Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Abstract

ABSTRACTClostridium difficileinfection (CDI) is an urgent public health concern causing considerable clinical and economic burdens. CDI can be treated with antibiotics, but recurrence of the disease following successful treatment of the initial episode often occurs. Surotomycin is a rapidly bactericidal cyclic lipopeptide antibiotic that is in clinical trials for CDI treatment and that has demonstrated superiority over vancomycin in preventing CDI relapse. Surotomycin is a structural analogue of the membrane-active antibiotic daptomycin. Previously, we utilizedin vitroserial passage experiments to deriveC. difficilestrains with reduced surotomycin susceptibilities. The parent strains used included ATCC 700057 and clinical isolates from the restriction endonuclease analysis (REA) groups BI and K. Serial passage experiments were also performed with vancomycin-resistant and vancomycin-susceptibleEnterococcus faeciumandEnterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility inC. difficileand enterococci. Illumina sequence data generated for the parent strains and serial passage isolates were compared. We identified nonsynonymous mutations in genes coding for cardiolipin synthase inC. difficileATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 inC. difficileREA type BI, and a PadR family transcriptional regulator inC. difficileREA type K. Among the 4 enterococcal strain pairs, 20 mutations were identified, and those mutations overlap those associated with daptomycin resistance. These data give insight into the mechanism of action of surotomycin againstC. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci.