The Posttranslocational Chaperone Lipoprotein PrsA Is Involved in both Glycopeptide and Oxacillin Resistance in Staphylococcus aureus
Open Access
- 1 July 2012
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 56 (7), 3629-3640
- https://doi.org/10.1128/aac.06264-11
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
This publication has 77 references indexed in Scilit:
- Functional analysis of the Listeria monocytogenes secretion chaperone PrsA2 and its multiple contributions to bacterial virulenceMolecular Microbiology, 2011
- Underestimation of Vancomycin and Teicoplanin MICs by Broth Microdilution Leads to Underdetection of Glycopeptide-Intermediate Isolates of Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2010
- Exploring innate glycopeptide resistance mechanisms in Staphylococcus aureusTrends in Microbiology, 2010
- Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axisProceedings of the National Academy of Sciences of the United States of America, 2010
- Genetic changes associated with glycopeptide resistance in Staphylococcus aureus: predominance of amino acid substitutions in YvqF/VraSRJournal of Antimicrobial Chemotherapy, 2009
- VanA-Type Vancomycin-ResistantStaphylococcus aureusAntimicrobial Agents and Chemotherapy, 2009
- Identification by Genomic and Genetic Analysis of Two New Genes Playing a Key Role in Intermediate Glycopeptide Resistance in Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2009
- Staphylococcus aureus PBP4 Is Essential for β-Lactam Resistance in Community-Acquired Methicillin-Resistant StrainsAntimicrobial Agents and Chemotherapy, 2008
- Role of VraSR in Antibiotic Resistance and Antibiotic-Induced Stress Response in Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2006
- The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophageNature, 1983