title: Carbapenem derivatives as potential inhibitors of various beta-lactamases, including class B metallo-beta-lactamases.
abstract: A variety of 1beta-methylcarbapenem derivatives were screened to identify inhibitors of IMP-1 metallo-beta-lactamase, a class B beta-lactamase, in an automated microassay system using nitrocefin as a substrate. The structure-inhibitory-activity relationship study revealed that three types of 1beta-methylcarbapenems having benzothienylthio, dithiocarbamate, or pyrrolidinylthio moieties at the C-2 position showed good inhibitory activity. Among the compounds screened, J-110,441, having a benzothienylthio moiety at the C-2 position of 1beta-methylcarbapenem, was the most potent inhibitor of class B metallo-beta-lactamases with K(i) values of 0. 0037, 0.23, 1.00, and 0.83 microM for IMP-1 encoded by the bla(IMP) gene, CcrA from Bacteroides fragilis, L1 from Stenotrophomonas maltophilia, and type II from Bacillus cereus, respectively. In a further characterization study, J-110,441 also showed inhibitory activity against TEM-type class A serine beta-lactamase and chromosomal class C serine beta-lactamase from Enterobacter cloacae with K(i) values of 2.54 and 0.037 microM, respectively. Combining imipenem or ceftazidime with J-110,441 had a synergistic effect on the antimicrobial activity against beta-lactamase-producing bacteria. Against the isolates of IMP-1-producing Serratia marcescens, the MICs of imipenem decreased to levels ranging from 1/64 to 1/4 in the presence of one-fourth of the MIC of J-110,441. Against E. cloacae producing high levels of class C beta-lactamase, the MIC of ceftazidime decreased from 64 to 4 microg/ml in the presence of 4 microg of J-110,441 per ml. This is the first report to describe a new class of inhibitor of class B and class C beta-lactamases including transferable IMP-1 metallo-beta-lactamases.
authors.affiliation: Banyu Tsukuba Research Institute, 3 Okubo, Tsukuba 300-2611, Japan. naganori@banyu.co.jp
authors.forename: R
authors.initials: R
authors.lastname: Nagano
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: H
authors.initials: H
authors.lastname: Imamura
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Hashizume
authors.forename: H
authors.initials: H
authors.lastname: Morishima
mesh_terms: D001426:Bacterial Proteins; D001441:Bacteroides fragilis / Q000187:drug effects / Q000201:enzymology; D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D015780:Carbapenems; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases