title: In vitro antibacterial activity and mechanism of action of J-111,225, a novel 1beta-methylcarbapenem, against transferable IMP-1 metallo-beta-lactamase producers.
abstract: IMP-1 beta-lactamase, a class B zinc metallo-enzyme encoded by the transferable bla(IMP) gene, is known to confer high-level resistance to carbapenems as well as to penicillins and cephalosporins. J-111, 225 is a novel 1beta-methylcarbapenem with a structurally unique side chain comprising a trans-3,5-disubstituted pyrrolidinylthio moiety at the C2 position. It inhibited 17 Serratia marcescens and two Pseudomonas aeruginosa IMP-1-producing clinical isolates at a concentration of 32 mg/L (range 4-32 mg/L). It showed synergy with imipenem against IMP-1-producing S. marcescens BB5886 and P. aeruginosa GN17203 with minimal FIC indices of 0.38 and 0.5, respectively. J-111,225 was more resistant than imipenem to hydrolysis by class B metallo-beta-lactamases. In kinetic studies, J-111,225 inhibited the IMP-I enzyme with a K(i) of 0.18 microM when imipenem was used as a substrate. In contrast, J-111,225 was the substrate for hydrolysis by other class B beta-lactamases such as Bacteroides fragilis CcrA, Stenotrophomonas maltophilia L1 and Bacillus cereus type II enzyme with respective K(m) values of 11, 10 and 148 microM. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the beta-lactamase.
authors.affiliation: Banyu Tsukuba Research Institute, Okubo 3, 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: T
authors.initials: T
authors.lastname: Hashizume
authors.forename: H
authors.initials: H
authors.lastname: Morishima
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology*; D001441:Bacteroides fragilis / Q000187:drug effects / Q000201:enzymology; D015780:Carbapenems / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015378:Imipenem / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D012706:Serratia marcescens / Q000187:drug effects / Q000201:enzymology; D013845:Thienamycins / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D004791:Enzyme Inhibitors; C404721:J 111225; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D015378:Imipenem