The in vitro activity of a new crystalline derivative of thienamycin, N-formimidoyl thienamycin (MK0787), was tested against 46 laboratory reference strains and 2,158 clinical isolates of gram-positive and -negative bacteria, including anaerobes, and compared with cefoxitin, cefazolin, carbenicillin, and amikacin. MK0787 was significantly more active than the reference antibiotics against most bacteria tested. MK0787 was 16-to 500-fold more active than the other antibiotics against Staphylococcus aureus, Streptococcus pneumoniae, and group A and group B streptococci, inhibiting most isolates at concentrations less than 0.031 ,ug/ml. The inhibition concentration against over 90% of 156 strains of Streptococcus faecalis was 1 yg/ml. MK0787 had slightly less activity than carbenicillin against Haemophilus influenzae. The minimal inhibitory concentrations of MK0787 against strains of Enterobacter spp., Citrobacter spp., Serratia marcescens, Pseudomonas aeruginosa, and Clostridium difficile that are resistant to currently available antibiotics were less than or equal to 4 ,ug/ml. The only species found resistant to MK0787 was Pseudomonas maltophilia, which was equally nonsusceptible to the other reference antibiotics.N-Formimidoyl thienamycin (MK0787) The strains of Neisseria gonorrhoeae were grown on chocolate agar plates, and colonies were suspended in Trypto-soy broth just before dilution.Mueller-Hinton agar (BBL Microbiology Systems) was used for susceptibility determinations unless otherwise specified. This medium supplemented with 5% sheep blood and Brucella agar (BBL Microbiology Systems) supplemented with 5% sheep blood and 10 ug of hemin per ml were used for determining the susceptibilities of streptococci and anaerobes, respectively. Chocolate Mueller-Hinton agar was used for H. influenzae and N. gonorrhoeae. An inoculum prepared by dilution of a fresh overnight broth culture was placed on susceptibility testing plates with a 27-prong metal replicater (Microplanter, Sakuma Seisakusho, Ltd.) of which each inoculation prong was 912 on May 11, 2018 by guest http://aac.asm.org/ Downloaded from

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A variety of 1β-methylcarbapenem derivatives were screened to identify inhibitors of IMP-1 metallo-β-lactamase, a class B β-lactamase, in an automated microassay system using nitrocefin as a substrate. The structure–inhibitory-activity relationship study revealed that three types of 1β-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 1β-methylcarbapenem, was the most potent inhibitor of class B metallo-β-lactamases with Ki values of 0.0037, 0.23, 1.00, and 0.83 μM for IMP-1 encoded by thebla 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 β-lactamase and chromosomal class C serine β-lactamase from Enterobacter cloacae withKi values of 2.54 and 0.037 μM, respectively. Combining imipenem or ceftazidime with J-110,441 had a synergistic effect on the antimicrobial activity against β-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 β-lactamase, the MIC of ceftazidime decreased from 64 to 4 μg/ml in the presence of 4 μg of J-110,441 per ml. This is the first report to describe a new class of inhibitor of class B and class C β-lactamases including transferable IMP-1 metallo-β-lactamases.

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