Mutations associated with reduced surotomycin susceptibility in Clostridium difficile and Enterococcus species.
Clostridium difficile infection (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 utilized in vitro serial passage experiments to derive C. difficile strains 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-susceptible Enterococcus faecium and Enterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility in C. difficile and 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 in C. difficile ATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 in C. difficile REA type BI, and a PadR family transcriptional regulator in C. difficile REA 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 against C. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci.
Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA.
Hannah M
HM
Adams
Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA.
Xiang
X
Li
Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
Carmela
C
Mascio
Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
Laurent
L
Chesnel
Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA kelli.palmer@utdallas.edu.
Kelli L
http://orcid.org/0000-0002-7343-9271
KL
Palmer
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D016360:Clostridioides difficile / Q000187:drug effects* / Q000235:genetics*; D019295:Computational Biology; D004269:DNA, Bacterial / Q000235:genetics / Q000302:isolation & purification; D017576:Daptomycin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D016983:Enterococcus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D010456:Peptides, Cyclic / Q000494:pharmacology*; D000091402:Prohibitins; D015183:Restriction Mapping; D020713:Vancomycin Resistance / Q000235:genetics
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C574454:CB-183,315; D004269:DNA, Bacterial; D055666:Lipopeptides; C000717331:PHB2 protein, human; D010456:Peptides, Cyclic; D000091402:Prohibitins; D017576:Daptomycin