Comparative study of the inhibition of metallo-beta-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group.
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.
Jin
Wanchun
W
Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe Honmachi, Japan.
Arakawa
Yoshichika
Y
Yasuzawa
Hisami
H
Taki
Tomoko
T
Hashiguchi
Ryo
R
Mitsutani
Kana
K
Shoga
Asumi
A
Yamaguchi
Yoshihiro
Y
Kurosaki
Hiromasa
H
Shibata
Naohiro
N
Ohta
Michio
M
Goto
Masafumi
M
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
D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D065093:beta-Lactamase Inhibitors; C409201:beta-lactamase IMP-1; C425108:beta-lactamase bla(vim-2); D001618:beta-Lactamases