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  • 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.
    Author: Nagano R, Adachi Y, Hashizume T, Morishima H.
    Journal: J Antimicrob Chemother; 2000 Mar; 45(3):271-6. PubMed ID: 10702544.
    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.
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