title: PBP2a mutations causing high-level Ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates.
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.
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: S Wesley
authors.initials: SW
authors.lastname: Long
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Shrenik C
authors.initials: SC
authors.lastname: Mehta
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Palzkill
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Cernoch
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA Department of Pharmacy, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Perez
authors.affiliation: Department of Pharmacy, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Musick
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Rosato
authors.affiliation: Center for Molecular and Translational Human Infectious Diseases Research, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Houston Methodist Research Institute, Houston, Texas, USA jmmusser@houstonmethodist.org.
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002511:Cephalosporins / Q000627:therapeutic use*; D003550:Cystic Fibrosis; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D051719:MutS DNA Mismatch-Binding Protein / Q000235:genetics; D046915:Penicillin-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D055815:Young Adult; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004269:DNA, Bacterial; D051719:MutS DNA Mismatch-Binding Protein; D046915:Penicillin-Binding Proteins; D000097583:Ceftaroline