Journal article
Identification of DraRS in Clostridioides difficile, a Two-Component Regulatory System That Responds to Lipid II-Interacting Antibiotics
Journal of bacteriology, Vol.205(10), e0016423
10/26/2023
DOI: 10.1128/jb.00164-23
PMCID: PMC10601625
PMID: 37439672
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.
Details
- Title: Subtitle
- Identification of DraRS in Clostridioides difficile, a Two-Component Regulatory System That Responds to Lipid II-Interacting Antibiotics
- Creators
- Anthony G Pannullo - University of IowaBrianne R Zbylicki - University of IowaCraig D Ellermeier - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of bacteriology, Vol.205(10), e0016423
- DOI
- 10.1128/jb.00164-23
- PMID
- 37439672
- PMCID
- PMC10601625
- ISSN
- 0021-9193
- eISSN
- 1098-5530
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R01AI087834; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R21AI159411; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: T32AI007511; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: T32GM008365
- Language
- English
- Electronic publication date
- 07/13/2023
- Date published
- 10/26/2023
- Academic Unit
- Microbiology and Immunology; Biology
- Record Identifier
- 9984444762802771
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