Role ofmgrAandsarAin Methicillin‐ResistantStaphylococcus aureusAutolysis 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.