Expression of mecA increases daptomycin tolerance in Staphylococcus aureus

Staphylococcus aureus is a leading cause of bacteremia, and infections caused by methicillin-resistant S. aureus (MRSA) strains are especially challenging to treat. MRSA strains are resistant to front-line beta-lactams due to PBP2a, a low-affinity penicillin-binding protein encoded by mecA. Daptomycin is used to treat MRSA infections but is not always effective. While daptomycin resistance has been well studied, the ability of S. aureus to tolerate daptomycin, a feature likely to slow clearance of the bacteria from the bloodstream, is less well understood. Here, using a panel of clinical bacteremia isolates, we show that MRSA strains are more tolerant of daptomycin than methicillin-susceptible S. aureus (MSSA) strains. This difference in tolerance is due to mecA and is independent of any changes in surface properties previously associated with altered daptomycin susceptibility. Instead, using a mecA transposon mutant, we found that a lack of this gene led to higher activity of the Agr quorum sensing system, resulting in an increased release of the phenol-soluble modulin toxins. Increased levels of these surfactant-like toxins prevented daptomycin from being inactivated by lipids released by the bacteria, leading to reduced antibiotic tolerance. Additionally, the clinical MRSA strains tested produced lower levels of toxins than the MSSA strains and inactivated daptomycin to a greater extent, explaining their enhanced tolerance. The expression of mecA in clinical MSSA strains reduced toxin production, increasing daptomycin inactivation and thereby enhancing tolerance. Together, these results demonstrate that mecA not only affects beta-lactam susceptibility but also compromises the efficacy of the last resort antibiotic daptomycin.