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Fifth-generation cephalosporins, ceftobiprole and ceftaroline, are promising drugs for treatment of bacterial infections from methicillin-resistant  Staphylococcus aureus  (MRSA). These antibiotics are able to bind native PBP2a, the penicillin-binding protein encoded by the  mecA  resistance determinant that mediates broad class resistance to nearly all other beta-lactam antibiotics, at clinically achievable concentrations. Mechanisms of resistance to ceftaroline based on  mecA  mutations have been previously described. Here we compare the genomes of 11 total parent-daughter strains of  Staphylococcus aureus  for which specific selection by serial passaging with ceftaroline or ceftobiprole was used to identify novel non- mecA  mechanisms of resistance. All 5 ceftaroline-resistant strains, derived from 5 different parental strains, contained mutations directly upstream of the  pbp4  gene (coding for the PBP4 protein), including four with the same thymidine insertion located 377 nucleotides upstream of the promoter site. In 4 of 5 independent ceftaroline-driven selections, we also isolated mutations to the same residue (Asn138) in PBP4. In addition, mutations in additional candidate genes such as  ClpX  endopeptidase,  PP2C  protein phosphatase and transcription terminator  Rho , previously undescribed in the context of resistance to ceftaroline or ceftobiprole, were detected in multiple selections. These genomic findings suggest that non- mecA  mechanisms, while yet to be encountered in the clinical setting, may also be important in mediating resistance to 5th-generation cephalosporins.

plos one

Whole-Genome Sequencing of Methicillin-Resistant Staphylococcus aureus Resistant to Fifth-Generation Cephalosporins Reveals Potential Non-mecA Mechanisms of Resistance