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Identification of a novel tedizolid resistance mutation in rpoB of MRSA after in vitro serial passage.
Shen, Tianwei; Penewit, Kelsi; Waalkes, Adam; Xu, Libin; Salipante, Stephen J; Nath, Abhinav; Werth, Brian J.
Afiliação
  • Shen T; Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA.
  • Penewit K; Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
  • Waalkes A; Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
  • Xu L; Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA.
  • Salipante SJ; Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
  • Nath A; Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA.
  • Werth BJ; Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA.
J Antimicrob Chemother ; 76(2): 292-296, 2021 01 19.
Article em En | MEDLINE | ID: mdl-33057715
OBJECTIVES: Tedizolid is an oxazolidinone antimicrobial with activity against Gram-positive bacteria, including MRSA. Tedizolid resistance is uncommon and tedizolid's capacity to select for cross-resistance to other antimicrobials is incompletely understood. The objective of this study was to further explore the phenotypic and genetic basis of tedizolid resistance in MRSA. METHODS: We selected for tedizolid resistance in an MRSA laboratory strain, N315, by serial passage until an isolate with an MIC ≥1 log2 dilution above the breakpoint for resistance (≥2 mg/L) was recovered. This isolate was subjected to WGS and susceptibility to a panel of related and unrelated antimicrobials was tested in order to determine cross-resistance. Homology modelling was performed to evaluate the potential impact of the mutation on target protein function. RESULTS: After 10 days of serial passage we recovered a phenotypically stable mutant with a tedizolid MIC of 4 mg/L. WGS revealed only one single nucleotide variant (A1345G) in rpoB, corresponding to amino acid substitution D449N. MICs of linezolid, chloramphenicol, retapamulin and quinupristin/dalfopristin increased by ≥2 log2 dilutions, suggesting the emergence of the so-called 'PhLOPSa' resistance phenotype. Susceptibility to other drugs, including rifampicin, was largely unchanged. Homology models revealed that the mutated residue of RNA polymerase would be unlikely to directly affect oxazolidinone action. CONCLUSIONS: To the best of our knowledge, this is the first time that an rpoB mutation has been implicated in resistance to PhLOPSa antimicrobials. The mechanism of resistance remains unclear, but is likely indirect, involving σ-factor binding or other alterations in transcriptional regulation.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxazolidinonas / Staphylococcus aureus Resistente à Meticilina Tipo de estudo: Diagnostic_studies / Prognostic_studies Idioma: En Revista: J Antimicrob Chemother Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxazolidinonas / Staphylococcus aureus Resistente à Meticilina Tipo de estudo: Diagnostic_studies / Prognostic_studies Idioma: En Revista: J Antimicrob Chemother Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos