Fidaxomicin resistance in Clostridioides difficile : a systematic review and predictive modeling with RNA polymerase binding sites.

Autor:	Le TM; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA., Eubank TA; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA., McKelvey AM; Department of Translational Medical Sciences, Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, USA., Cao X; Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas, USA., Hurdle JG; Department of Translational Medical Sciences, Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, USA., Garey KW; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Dec 05; Vol. 68 (12), pp. e0120624. Date of Electronic Publication: 2024 Nov 06.
DOI:	10.1128/aac.01206-24
Abstrakt:	Fidaxomicin (FDX), an RNA polymerase (RNAP) inhibitor antibiotic, is a guideline-recommended therapy for Clostridioides difficile infection. Mutations associated with reduced FDX minimum inhibitory concentrations (MICs) have been identified. However, the molecular characterization of these mutations on FDX binding and the development of FDX resistance have not been studied. The purpose of this systematic review was to identify FDX resistance in C. difficile isolates and determine whether single nucleotide polymorphisms associated with increased FDX MIC aligned with the RNAP binding pocket interacting residues. A systematic literature search was done in PubMed (1991-2023) with identified articles and their bibliographies searched for papers that included C. difficile genetic mutations and increased FDX MIC. Visualization of FDX-RNAP interactions was performed on Schrödinger Maestro using the publicly available C. difficile RNAP with fidaxomicin sequence (code 7L7B) on the Protein Data Bank. Seven articles were identified after applying inclusion and exclusion criteria. The most common mutation in clinical and laboratory isolates was at position V1143 of the β subunit, which accounted for approximately 50% of the identified mutations. Most other mutations occurred within the β' subunit of RNAP. Approximately one-third of the identified mutation aligned directly with FDX interacting residues with C. difficile RNAP (7/20) with most of the remainder occurring within 5 Å of the binding residues. C. difficile strains with elevated FDX MIC align closely with the known RNAP binding residues. These data demonstrate the potential to identify genomic methods to identify emerging FDX resistance. Competing Interests: K.W.G. has received research funding from Merck, Acurx, and Paratek Pharmaceuticals. All other authors report no conflict.
Databáze:	MEDLINE
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