Fate of mutation rate depends on agr locus expression during oxacillin-mediated heterogeneous-homogeneous selection in methicillin-resistant Staphylococcus aureus clinical strains

Konrad B. Plata, Roberto R. Rosato, Adriana E. Rosato

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) strains are characterized by a heterogeneous expression of resistance. We have previously shown in clinical oxacillin-susceptible, mecA-positive MRSA strains that selection from a very heterogeneous (HeR) to highly homogeneous (HoR) resistant phenotype was mediated by acquisition of mutations through an oxacillin-induced SOS response. In the present study, we used a spotted DNA microarray to evaluate differential gene expression during HeR-HoR selection and found increased expression of the agr two-component regulatory system. We hypothesized that increased expression of agr represents a mechanistically relevant component of this process. We demonstrated that inactivation of agr during the HeR-HoR selection process results in a significant increase in mutation rate; these effects were reversed by complementing the agr mutant. Furthermore, we found that extemporal ectopic expression of agr and, more specifically, RNAII in agr-null mutant HeR cells suppressed mutation frequency and the capacity of these cells to undergo the HeR-HoR selection. These findings sustain the concept that increased expression of agr during HeR-HoR selection plays a critical role in regulating the β-lactam-induced increased mutation rate in very heterogeneous MRSA strains. Moreover, they indicate that a temporally controlled increase in agr expression is required to tightly modulate SOS-mediated mutation rates, which then allows for full expression of oxacillin homogeneous resistance in very heterogeneous clinical MRSA strains.

Original languageEnglish (US)
Pages (from-to)3176-3186
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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