title: Comparative study of the inhibition of metallo-beta-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group.
abstract: For the purpose of screening of inhibitors that are effective for wide range of metallo-beta-lactamases, the inhibitory effect of two series of compounds, 2-omega-phenylalkyl-3-mercaptopropionic acid (PhenylCnSH (n=1-4)) and N-[(7-chloro-quinolin-4-ylamino)-alkyl]-3-mercapto-propionamide (QuinolineCnSH (n=2-6)), where n denotes the alkyl chain length, on metallo-beta-lactamases IMP-1 and VIM-2 was examined. These inhibitors contain a thiol group and a hydrophobic group linked by variable-length methylene chain. PhenylCnSH (n=1-4) was found to be a potent inhibitor of both IMP-1 and VIM-2. PhenylC4SH was the potent inhibitor of both IMP-1 (IC(50)=1.2 microM) and VIM-2 (IC(50)=1.1 microM) among this study. When the number of methylene units was varied, QuinolineC4SH showed the maximum inhibitory activity against IMP-1 and VIM-2 (IC(50)=2.5 microM and IC(50)=2.4 microM). The relationship between the inhibitory effect of the alkyl chain length was different for both series of inhibitors, suggesting that IMP-1 has a tighter binding site than VIM-2. QuinolineCnSH did not serve as a fluorescence reagent for metallo-beta-lactamases.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe Honmachi, Japan.
authors.forename: Wanchun
authors.initials: W
authors.lastname: Jin
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Arakawa
authors.forename: Hisami
authors.initials: H
authors.lastname: Yasuzawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Taki
authors.forename: Ryo
authors.initials: R
authors.lastname: Hashiguchi
authors.forename: Kana
authors.initials: K
authors.lastname: Mitsutani
authors.forename: Asumi
authors.initials: A
authors.lastname: Shoga
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Kurosaki
authors.forename: Naohiro
authors.initials: N
authors.lastname: Shibata
authors.forename: Michio
authors.initials: M
authors.lastname: Ohta
authors.forename: Masafumi
authors.initials: M
authors.lastname: Goto
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D065093:beta-Lactamase Inhibitors; C409201:beta-lactamase IMP-1; C425108:beta-lactamase bla(vim-2); D001618:beta-Lactamases