Emergence of highly-oxacillin resistant MRSA strains carrying the mecC determinant

Most MRSA strains are resistant to beta-lactam antibiotics due to the presence of the mecA gene encoding an extra penicillin-binding protein (PBP2A) that has low affinity to virtually all beta-lactam antibiotics. Recently, a new resistance determinant – the mecC gene – was identified in S. aureus isolates recovered from humans and dairy cattle. Although having typically low MICs to beta-lactam antibiotics, MRSA strains with the mecC determinant are also capable of expressing high levels of oxacillin resistance when in an optimal genetic background. In order to test the impact of extensive beta-lactam selection on the emergence of mecC carrying strains with high levels of antibiotic resistance, we exposed the prototype mecC MRSA strain LGA251 to increasing concentrations of oxacillin. LGA251 was able to rapidly adapt to high concentrations of oxacillin in the growth medium. In such laboratory mutants with increased levels of oxacillin resistance, we identified mutations in genes with no relationship to the mecC regulatory system indicating that the genetic background plays an important role in the establishment of the levels of oxacillin resistance. Our data also indicate that the stringent stress response plays a critical role in the beta-lactam antibiotic resistant phenotype of MRSA strains carrying the mecC determinant.