Carbapenem derivatives as potential inhibitors of various beta-lactamases,including class B metallo-beta-lactamases

A variety of 1 beta-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 1 beta -methylcarbapenems having benzothienylthio, dithiocarbamate, or pyrrolidiny lthio moieties at the C-2 position shelved good inhibitory activity. Among the compounds screened, J-110,441, having a benzothienylthio moiety at the C-2 position of 1 beta-methylcarbapenen, was the most potent inhibitor of c lass B metallo-beta-lactamases with K-i values of 0.0037, 0.23, 1.00, and 0 .83 mu M for IMP-1 encoded by the bla(IMP) gene, CcrA from Bacteroides frag ilis, L1 from Stenotrophomonas maltophilia, and type II from Bacillus cereu s, respectively. In a further characterization study, J-110,441 also showed inhibitory activity against TEM-type class A serine beta-lactamase and chr omosomal class C serine beta-lactamase from Enterobacter cloacae with K-i v alues of 2.54 and 0.037 mu M, respectively. Combining imipenem or ceftazidi me ith J-110,441 had a synergistic effect on the antimicrobial activity aga inst beta-lactamase-producing bacteria. Against the isolates of IMP-1-produ cing 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. Aga inst E. cloacae producing high levels of class C beta-lactamase, the MIC of ceftazidime decreased from 64 to 4 mu g/ml in the presence of 4 mu g of J- 110,441 per ml. This is the first report to describe a new class of inhibit or of class B and class C beta-lactamases including transferable IMP-1 meta llo-beta-lactamases.