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• W4384119694 abstract "Clostridioides difficile is a Gram-positive opportunistic pathogen that results in 220,000 infections, 12,000 deaths, and upwards of $1 billion in medical costs in the United States each year. C. difficile is highly resistant to a variety of antibiotics, but we have a poor understanding of how C. difficile senses and responds to antibiotic stress and how such sensory systems affect clinical outcomes. We have identified a spontaneous C. difficile mutant that displays increased daptomycin resistance. We performed whole-genome sequencing and found a nonsense mutation, S605*, in draS, which encodes a putative sensor histidine kinase of a two-component system (TCS). The draSS605* mutant has an ~4- to 8-fold increase in the daptomycin MIC compared to the wild type (WT). We found that the expression of constitutively active DraRD54E in the WT increases daptomycin resistance 8- to 16-fold and increases bacitracin resistance ~4-fold. We found that a selection of lipid II-inhibiting compounds leads to the increased activity of the luciferase-based reporter PdraR-slucopt, including vancomycin, bacitracin, ramoplanin, and daptomycin. Using RNA sequencing (RNA-seq), we identified the DraRS regulon. Interestingly, we found that DraRS can induce the expression of the previously identified hex locus required for the synthesis of a novel glycolipid produced in C. difficile. Our data suggest that the induction of the hex locus by DraR explains some, but not all, of the DraR-induced daptomycin and bacitracin resistance. IMPORTANCE Clostridioides difficile is a major cause of hospital-acquired diarrhea and represents an urgent concern due to the prevalence of antibiotic resistance and the rate of recurrent infections. C. difficile encodes ~50 annotated two-component systems (TCSs); however, only a few have been studied. The function of these unstudied TCSs is not known. Here, we show that the TCS DraRS plays a role in responding to a subset of lipid II-inhibiting antibiotics and mediates resistance to daptomycin and bacitracin in part by inducing the expression of the recently identified hex locus, which encodes enzymes required for the production of a novel glycolipid in C. difficile." @default.
• W4384119694 created "2023-07-14" @default.
• W4384119694 creator A5003697204 @default.
• W4384119694 creator A5060823833 @default.
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• W4384119694 date "2023-07-13" @default.
• W4384119694 modified "2023-10-01" @default.
• W4384119694 title "Identification of DraRS in Clostridioides difficile, a Two-Component Regulatory System That Responds to Lipid II-Interacting Antibiotics" @default.
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• W4384119694 doi "https://doi.org/10.1128/jb.00164-23" @default.
• W4384119694 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37439672" @default.
• W4384119694 hasPublicationYear "2023" @default.
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