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The posttranslocational chaperone lipoprotein PrsA is involved in both glycopeptide and oxacillin resistance in Staphylococcus aureus

Published in Antimicrobial Agents and Chemotherapy. 2012, vol. 56, no. 7, p. 3629-3640
Abstract Understanding in detail the factors which permit Staphylococcus aureus to counteract cell wall-active antibiotics is a prerequisite to elaborating effective strategies to prolong the usefulness of these drugs and define new targets for pharmacological intervention. Methicillin-resistant S. aureus (MRSA) strains are major pathogens of hospital-acquired and community-acquired infections and are most often treated with glycopeptides (vancomycin and teicoplanin) because of their resistance to most penicillins and a limited arsenal of clinically proven alternatives. In this study, we examined PrsA, a lipid-anchored protein of the parvulin PPIase family (peptidyl-prolyl cis/trans isomerase) found ubiquitously in all Gram-positive species, in which it assists posttranslocational folding at the outer surface of the cytoplasmic membrane. We show by both genetic and biochemical assays that prsA is directly regulated by the VraRS two-component sentinel system of cell wall stress. Disruption of prsA is tolerated by S. aureus, and its loss results in no detectable overt macroscopic changes in cell wall architecture or growth rate under nonstressed growth conditions. Disruption of prsA leads, however, to notable alterations in the sensitivity to glycopeptides and dramatically decreases the resistance of COL (MRSA) to oxacillin. Quantitative transcriptional analysis reveals that prsA and vraR are coordinately upregulated in a panel of stable laboratory and clinical glycopeptide-intermediate S. aureus (GISA) strains compared to their susceptible parents. Collectively, our results point to a role for prsA as a facultative facilitator of protein secretion or extracellular folding and provide a framework for understanding why prsA is a key element of the VraRS-mediated cell wall stress response.
Keywords Bacterial Proteins/genetics/metabolismDrug Resistance, Bacterial/geneticsElectrophoretic Mobility Shift AssayGlycopeptides/pharmacologyLipoproteins/genetics/metabolismMembrane Proteins/genetics/metabolismMicroscopy, Electron, TransmissionOxacillin/pharmacologyReverse Transcriptase Polymerase Chain ReactionStaphylococcus aureus/drug effects/genetics/metabolism/ultrastructure
PMID: 22526301
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Research groups Acquisition et expression de facteurs de virulence chez Staphylococcus aureus (86)
Génétique et biologie moléculaire des infections à Staphylococcus aureus (667)
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JOUSSELIN, Ambre et al. The posttranslocational chaperone lipoprotein PrsA is involved in both glycopeptide and oxacillin resistance in Staphylococcus aureus. In: Antimicrobial Agents and Chemotherapy, 2012, vol. 56, n° 7, p. 3629-3640. doi: 10.1128/AAC.06264-11 https://archive-ouverte.unige.ch/unige:32458

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Deposited on : 2013-12-18

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