MRSA: laboratory evolution to disentangle complex vancomycin adaptation trajectories

Infections with methicillin-resistant Staphylococcus aureus (MRSA) are associated with significant morbidity and mortality. Vancomycin is a last-line antibiotic used to treat MRSA infections; however, strains with decreased susceptibility to vancomycin (vancomycin-intermediate S. aureus [VISA]) have been spreading, and VISA infections are associated with prolonged therapeutic treatment and treatment failure. To map out the evolutionary trajectory behind VISA development, we characterized the mutational, transcriptional, and phenotypic landscape of 10 lineages of S. aureus USA300 strain JE2 that evolved in parallel to vancomycin. We demonstrate that MRSA strains adapt to vancomycin by divergent pathways leading to high or low oxacillin susceptibility characterized by mutational or transcriptional profiles. Our results point to diagnostic possibilities that may support personalized antibiotic treatment regimes.