title: In vitro and in vivo antistaphylococcal activities of L-695,256, a carbapenem with high affinity for the penicillin-binding protein PBP 2a.
abstract: L-695,256 is a synthetic carbapenem beta-lactam antibiotic that binds with a high degree of affinity to penicillin-binding protein (PBP) PBP 2a, the protein that mediates staphylococcal resistance to methicillin. The concentration of L-695,256 that inhibited binding of radiolabeled [3H]penicillin to PBP 2a by 50% was 1.2 micrograms/ml, whereas they were 14 and 68 micrograms/ml for penicillin and imipenem, respectively. Cell wall synthesis, determined by incorporation of [14C]N-acetylglucosamine into whole cells, was inhibited by 50% at concentrations of 1.3, 26, and 132 micrograms/ml for L-695,256, penicillin, and imipenem, respectively, for the methicillin-resistant strain COL. Growth of cells of each of two homogeneously resistant strains, COL and 76, was completely inhibited by 4 micrograms of L-695,256 per ml, whereas growth was inhibited by 100 micrograms or more of penicillin or imipenem per ml. The efficacies of L-695,256 (10 mg/kg given three times daily [t.i.d.]), imipenem (37.5 mg/kg t.i.d.), penicillin (300,000 units/kg t.i.d.), and vancomycin (25 mg/kg given twice daily) were compared in the rabbit model of aortic valve endocarditis established with these homogeneous strains. After 4 days of treatment, mean bacterial densities in aortic valve vegetations were reduced by 4.0 to 5.8 log10 CFU/g for L-695,256, 1.0 to 1.8 log10 CFU/g for imipenem, -1.1 to 3.9 log10 CFU/g for penicillin, and 1.1 to 3.0 log10 CFU/g for vancomycin in comparison to the densities of controls. Compounds such as L-695,256 that are bound by PBP 2a with a high degree of affinity are likely to be extremely effective in the treatment of infections caused by methicillin-resistant staphylococci.
authors.affiliation: Medical Service, San Francisco General Hospital, California, USA.
authors.forename: H F
authors.initials: HF
authors.lastname: Chambers
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D015780:Carbapenems / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism; D004697:Endocarditis, Bacterial / Q000188:drug therapy; D006602:Hexosyltransferases; D007093:Imidazoles / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D015780:Carbapenems; D002352:Carrier Proteins; D007093:Imidazoles; C093180:L 695256; D046915:Penicillin-Binding Proteins; D014640:Vancomycin; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase