The roles of mprF mutation contribute to cross-resistance between daptomycin and vancomycin. Staphylococcus aureus

Daptomycin (DAP) and vancomycin (VCM) are antibiotics used to treat methicillin-resistant Staphylococcus aureus (MRSA). Despite different mechanisms our group have firstly reported on cross-resistance to both antibiotics, causing restricted options of treatment for infections. So far, the mechanism of this cross-resistance is still unknown. The purpose in this study is to elucidate the mechanisms of DAP/VCM cross-resistance in MRSA. 12 sets of DAP-susceptible (DS) and -nonsusceptible (DNS) MRSA isolates from medical institutions in Japan were collected from the same patient before and after DAP treatment. Antibiotic susceptibility profiling and genomic comparison showed that MRSA strain with single resistance to DAP (1 set) carry only lacF mutation, while mprF mutation was identified in all DNS strains belonging to the remaining 11 sets of MRSA isolates. The mprF mutation was then introduced into DS strain and the generated mutant was found to exhibit DAP/VCM cross-resistance, suggesting that mprF mutation contributes to DAP/VCM cross-resistance in MRSA. In addition, all DNS strains carrying mprF mutation showed alteration of surface charge with increased positive-charge membrane compared with DS strains. Thus, DAP/VCM cross-resistant mechanism in MRSA is proposed to be associated with alteration of membrane surface charge mediated by mprF.