title: Binding affinity for penicillin-binding protein 2a correlates with in vivo activity of beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus.
abstract: The beta-lactam antibiotics ticarcillin, nafcillin, imipenem, and ampicillin, which differ in antibacterial activity against methicillin-resistant strains of Staphylococcus aureus, were examined for affinity to penicillin-binding protein (PBP) 2a, which mediates methicillin resistance. The relative efficacy of each antibiotic was compared to vancomycin in a rabbit model of aortic valve endocarditis caused by either a methicillin-susceptible or methicillin-resistant strain of beta-lactamase-producing S. aureus. beta-lactamase inhibitors clavulanate and sulbactam were used in combination with ticarcillin and ampicillin, respectively. All beta-lactam antibiotics were effective against the susceptible strain. beta-lactam antibiotic activity in vitro and in vivo against the resistant strain correlated with its affinity for binding to PBP 2a. Lack of efficacy of beta-lactam antibiotics for the resistant strain was due to an inability to eradicate the resistant subpopulation of cells. Vancomycin was the most effective agent.
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: H F
authors.initials: HF
authors.lastname: Chambers
authors.forename: M
authors.initials: M
authors.lastname: Sachdeva
authors.forename: S
authors.initials: S
authors.lastname: Kennedy
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000667:Ampicillin / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins; D002352:Carrier Proteins; D004195:Disease Models, Animal; D004697:Endocarditis, Bacterial / Q000188:drug therapy; D006602:Hexosyltransferases / Q000378:metabolism*; D015378:Imipenem / Q000378:metabolism / Q000494:pharmacology; D008712:Methicillin / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D002267:Muramoylpentapeptide Carboxypeptidase; D009254:Nafcillin / Q000378:metabolism / Q000494:pharmacology; D010403:Penicillin Resistance; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases / Q000378:metabolism*; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013982:Ticarcillin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D009097:Multienzyme Complexes; D046915:Penicillin-Binding Proteins; D009254:Nafcillin; D015378:Imipenem; D000667:Ampicillin; D000217:Acyltransferases; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D013982:Ticarcillin; D008712:Methicillin