Expression of mecA reduces the daptomycin susceptibility of Staphylococcus aureus

Staphylococcus aureus is a leading cause of bacteraemia and infections caused by methicillin-resistant strains (MRSA) 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 and is associated with high rates of morbidity and mortality. Understanding why daptomycin fails is crucial to devising strategies to improve treatment outcomes. Here, using a panel of clinical bacteraemia isolates, we show that MRSA strains are less susceptible to daptomycin than methicillin-susceptible (MSSA) strains. This difference in susceptibility was due to mecA and was 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 enhanced susceptibility to the antibiotic. Additionally, the clinical MRSA strains tested produced lower levels of toxins than the MSSA strains and inactivated daptomycin to a greater extent, explaining their reduced susceptibility. Expression of mecA in clinical MSSA strains reduced toxin production, increasing daptomycin inactivation and thereby enhancing survival. Together, these results demonstrate that mecA does not only affect beta-lactam susceptibility but also compromises the efficacy of the last resort antibiotic daptomycin.