1. PBP2a Mutations Causing High-Level Ceftaroline Resistance in Clinical Methicillin-Resistant Staphylococcus aureus Isolates
- Author
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Patricia L. Cernoch, Katherine K. Perez, Randall J. Olsen, Timothy Palzkill, Adriana E. Rosato, S. Wesley Long, Shrenik C. Mehta, William L. Musick, and James M. Musser
- Subjects
Adult ,DNA, Bacterial ,Male ,Methicillin-Resistant Staphylococcus aureus ,Cystic Fibrosis ,medicine.drug_class ,Cephalosporin ,Microbial Sensitivity Tests ,Drug resistance ,Biology ,medicine.disease_cause ,Cystic fibrosis ,Bacterial genetics ,Microbiology ,Young Adult ,Mechanisms of Resistance ,Drug Resistance, Bacterial ,medicine ,Humans ,Penicillin-Binding Proteins ,Pharmacology (medical) ,Pharmacology ,Binding Sites ,Base Sequence ,Sequence Analysis, DNA ,Staphylococcal Infections ,medicine.disease ,Methicillin-resistant Staphylococcus aureus ,Virology ,MutS DNA Mismatch-Binding Protein ,Anti-Bacterial Agents ,Cephalosporins ,Infectious Diseases ,Amino Acid Substitution ,Isogenic mutant ,Staphylococcus aureus ,Molecular mechanism - Abstract
Ceftaroline is the first member of a novel class of cephalosporins approved for use in the United States. Although prior studies have identified eight ceftaroline-resistant methicillin-resistant Staphylococcus aureus (MRSA) isolates in Europe and Asia with MICs ranging from 4 to 8 mg/liter, high-level resistance to ceftaroline (>32 mg/liter) has not been described in MRSA strains isolated in the United States. We isolated a ceftaroline-resistant (MIC > 32 mg/liter) MRSA strain from the blood of a cystic fibrosis patient and five MRSA strains from the respiratory tract of this patient. Whole-genome sequencing identified two amino acid-altering mutations uniquely present in the ceftaroline-binding pocket of the transpeptidase region of penicillin-binding protein 2a (PBP2a) in ceftaroline-resistant isolates. Biochemical analyses and the study of isogenic mutant strains confirmed that these changes caused ceftaroline resistance. Thus, we identified the molecular mechanism of ceftaroline resistance in the first MRSA strain with high-level ceftaroline resistance isolated in the United States.
- Published
- 2014
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