Role of mgrA and sarA in methicillin-resistant Staphylococcus aureus autolysis and resistance to cell wall-active antibiotics.

BACKGROUND We have previously shown the importance of mgrA and sarA in controlling autolysis of Staphylococcus aureus, with MgrA and SarA both being negative regulators of murein hydrolases. METHODS In this study, we analyzed the effects of mgrA and sarA on antibiotic-mediated lysis in vitro and on the responses to cell wall-active antibiotic therapy in an experimental endocarditis model by use of 2 representative MRSA strains: the laboratory strain COL and the community-acquired clinical strain MW2. RESULTS We found that mgrA and sarA independently down-regulated sarV (a marker for autolysis), although the alteration in sarV expression did not correlate directly with the autolysis profiles of single mgrA and sarA mutants. Importantly, the mgrA/sarA double mutants of both strains were more autolytic than the single mutants in vitro. We demonstrated that, despite equivalent intrinsic virulences of the parent strains and their isogenic mgrA/sarA double mutants in the endocarditis model, oxacillin and vancomycin treatment of the mgrA/sarA double mutants yielded significant reductions in vegetation bacterial densities in vivo, compared with treatment of their respective parent strains. CONCLUSIONS These results suggest that down-regulation of mgrA/sarA in combination with use of cell wall-active antibiotics may represent a novel approach to treat MRSA infections.