title: The Staphylococcus aureus thiol/oxidative stress global regulator Spx controls trfA, a gene implicated in cell wall antibiotic resistance.
abstract: S. aureus combats cell wall antibiotic stress by altered gene expression mediated by various environmental signal sensors. In this study, we examined the transcriptional regulation of trfA, a gene related to mecA of Bacillus subtilis encoding an adaptor protein implicated in multiple roles, notably, proteolysis and genetic competence. Despite strong sequence similarity to B. subtilis mecA, the function of S. aureus trfA remains largely unexplored; however, its deletion leads to almost complete loss of resistance to oxacillin and glycopeptide antibiotics in glycopeptide-intermediate S. aureus (GISA) derivatives of methicillin-susceptible or methicillin-resistant S. aureus (MRSA) clinical or laboratory isolates. Northern blot analysis and 5' rapid amplification of cDNA ends (RACE) mapping revealed that trfA was expressed monocistronically by three promoters. Cell wall-active antibiotic exposure led to both increased trfA transcription and enhanced steady-state TrfA levels. trfA promoter regulation was not dependent upon the cell wall stress sentinel VraSR and other sensory stress systems, such as GraRS, WalkRK, Stk1/Stp1, and SigB. Notably, we discovered that the global oxidative-stress regulator Spx controlled trfA transcription. This finding was also confirmed using a strain with enhanced Spx levels resulting from a defect in yjbH, encoding a Spx-interacting protein governing Spx proteolytic degradation. A cohort of clinical GISA strains revealed significant steady-state upregulation of trfA compared to corresponding susceptible parental strains, further supporting a role for trfA in antibiotic resistance. These data provide strong evidence for a link between cell wall antibiotic stress and evoked responses mediated by an oxidative-stress sensor.
authors: Service of Infectious Diseases, University Hospital and Medical School of Geneva, Geneva, Switzerland.
authors: Ambre
authors: A
authors: Jousselin
authors: William L
authors: WL
authors: Kelley
authors: Christine
authors: C
authors: Barras
authors: Daniel P
authors: DP
authors: Lew
authors: Adriana
authors: A
authors: Renzoni
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002473:Cell Wall / Q000187:drug effects / Q000235:genetics*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial; D008565:Membrane Proteins / Q000235:genetics*; D016106:Methicillin Resistance / Q000235:genetics; D008969:Molecular Sequence Data; D010068:Oxacillin / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins; D013438:Sulfhydryl Compounds; D010068:Oxacillin
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