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Whole genome sequencing and complete genetic analysis reveals novel pathways to glycopeptide resistance in Staphylococcus aureus.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Renzoni Adriana, Andrey Diego O, Jousselin Ambre, Barras Christine, Monod Antoinette, Vaudaux Pierre, Lew Daniel, Kelley William L,
Project Mécanismes moléculaires de la resistance intermédiaire aux glycopeptides chez les staphyloques dorés
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Original article (peer-reviewed)

Journal PloS one
Volume (Issue) 6(6)
Page(s) 21577 - 21577
Title of proceedings PloS one
DOI 10.1371/journal.pone.0021577

Abstract

The precise mechanisms leading to the emergence of low-level glycopeptide resistance in Staphylococcus aureus are poorly understood. In this study, we used whole genome deep sequencing to detect differences between two isogenic strains: a parental strain and a stable derivative selected stepwise for survival on 4 µg/ml teicoplanin, but which grows at higher drug concentrations (MIC 8 µg/ml). We uncovered only three single nucleotide changes in the selected strain. Nonsense mutations occurred in stp1, encoding a serine/threonine phosphatase, and in yjbH, encoding a post-transcriptional negative regulator of the redox/thiol stress sensor and global transcriptional regulator, Spx. A missense mutation (G45R) occurred in the histidine kinase sensor of cell wall stress, VraS. Using genetic methods, all single, pairwise combinations, and a fully reconstructed triple mutant were evaluated for their contribution to low-level glycopeptide resistance. We found a synergistic cooperation between dual phospho-signalling systems and a subtle contribution from YjbH, suggesting the activation of oxidative stress defences via Spx. To our knowledge, this is the first genetic demonstration of multiple sensor and stress pathways contributing simultaneously to glycopeptide resistance development. The multifactorial nature of glycopeptide resistance in this strain suggests a complex reprogramming of cell physiology to survive in the face of drug challenge.
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