Journal article
Identification of Clostridioides difficile mutants with increased daptomycin resistance
Journal of bacteriology, Vol.206(3), e0036823
03/21/2024
DOI: 10.1128/jb.00368-23
PMCID: PMC10955854
PMID: 38376203
Abstract
Daptomycin is a cyclic lipopeptide antibiotic used to treat infections caused by some Gram-positive bacteria. Daptomycin disrupts synthesis of the peptidoglycan (PG) cell wall by inserting into the cytoplasmic membrane and binding multiple forms of the undecaprenyl carrier lipid required for PG synthesis. Membrane insertion requires phosphatidylglycerol, so studies of daptomycin can provide insight into assembly and maintenance of the cytoplasmic membrane. Here, we studied the effects of daptomycin on Clostridioides difficile, the leading cause of healthcare-associated diarrhea. We observed that growth of C. difficile strain R20291 in the presence of sub-MIC levels of daptomycin resulted in a chaining phenotype, minicell formation, and lysis—phenotypes broadly consistent with perturbation of membranes and PG synthesis. We also selected for and characterized eight mutants with elevated daptomycin resistance. The mutations in these mutants were mapped to four genes: cdsA (cdr20291_2041), ftsH2 (cdr20291_3396), esrR (cdr20291_1187), and draS (cdr20291_2456). Of these four genes, only draS has been characterized previously. Follow-up studies indicate these mutations confer daptomycin resistance by two general mechanisms: reducing the amount of phosphatidylglycerol in the cytoplasmic membrane (cdsA) or altering the regulation of membrane processes (ftsH2, esrR, and draS). Thus, the mutants described here provide insights into phospholipid synthesis and identify signal transduction systems involved in cell envelope biogenesis and stress response in C. difficile.
Details
- Title: Subtitle
- Identification of Clostridioides difficile mutants with increased daptomycin resistance
- Creators
- Brianne R Zbylicki - University of IowaClaire E Murphy - University of IowaJennifer A Petsche - University of IowaUte Müh - University of IowaHoria A Dobrila - University of IowaTheresa D Ho - University of IowaMikaela N Daum - University of IowaAnthony G Pannullo - University of IowaDavid S Weiss - University of IowaCraig D Ellermeier - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of bacteriology, Vol.206(3), e0036823
- DOI
- 10.1128/jb.00368-23
- PMID
- 38376203
- PMCID
- PMC10955854
- ISSN
- 0021-9193
- eISSN
- 1098-5530
- Grant note
- DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R01AI087834, R21AI159411
- Language
- English
- Electronic publication date
- 02/20/2024
- Date published
- 03/21/2024
- Academic Unit
- Microbiology and Immunology; Biology
- Record Identifier
- 9984560419502771
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