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Greninger, AL, Chatterjee, SS, Chan, LC, Hamilton, SM, Chambers, HF and Chiu, CY (2016) Whole-Genome Sequencing of Methicillin-Resistant Staphylococcus aureus Resistant to Fifth-Generation Cephalosporins Reveals Potential Non-mecA Mechanisms of Resistance. PLoS ONE 11:e0149541


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.


PubMed PMC4758708 Online version:10.1371/journal.pone.0149541




Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status


GO:0008233: peptidase activity



Figure 1 shows that the left panel shows the entire complex, whereas the right panel shows a zoomed image of the cephalosporin binding pocket. The Staphylococcus aureus strain depicted in the crystal structure (PDB 3HUM) [30], Col, is the parental strain of the Colnex strain used in the current study (Table 1). Mutant residues in PBP4 identified by selection with ceftaroline or ceftobiprole are highlighted in blue. The ligand marked in yellow is cefotaxime.

Missing: with/from
CACAO 11355


See also


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