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Antimicrobial Agents and Chemotherapy, October 1999, p. 2497-2503, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Carbapenem Derivatives as Potential Inhibitors of Various beta -Lactamases, Including Class B Metallo-beta -Lactamases

Rie Nagano,* Yuka Adachi, Hideaki Imamura, Koji Yamada, Terutaka Hashizume, and Hajime Morishima

Banyu Tsukuba Research Institute, 3 Okubo, Tsukuba 300-2611, Japan

Received 15 March 1999/Returned for modification 30 May 1999/Accepted 4 August 1999

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 Ki values of 0.0037, 0.23, 1.00, and 0.83 µM for IMP-1 encoded by the blaIMP 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 Ki 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 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 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 beta -lactamases including transferable IMP-1 metallo-beta -lactamases.

* Corresponding author. Mailing address: Banyu Tsukuba Research Institute, 3 Okubo, Tsukuba 300-2611, Japan. Phone: 81-298-77-2000. Fax: 81-298-77-2029. E-mail: naganori{at}banyu.co.jp.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2497-2503, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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