Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-beta-lactamase.
IMP-1 metallo-beta-lactamase (class B) is a plasmid-borne zinc metalloenzyme that efficiently hydrolyzes beta-lactam antibiotics, including carbapenems, rendering them ineffective. Because IMP-1 has been found in several clinically important carbapenem-resistant pathogens, there is a need for inhibitors of this enzyme that could protect broad spectrum antibiotics such as imipenem from hydrolysis and thus extend their utility. We have identified a series of 2,3-(S,S)-disubstituted succinic acids that are potent inhibitors of IMP-1. Determination of high resolution crystal structures and molecular modeling of succinic acid inhibitor complexes with IMP-1 has allowed an understanding of the potency, stereochemistry, and structure-activity relationships of these inhibitors.
Toney
J H
JH
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. jeff_toney@merck.com
Hammond
G G
GG
Fitzgerald
P M
PM
Sharma
N
N
Balkovec
J M
JM
Rouen
G P
GP
Olson
S H
SH
Hammond
M L
ML
Greenlee
M L
ML
Gao
Y D
YD
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D010957:Plasmids; D013386:Succinates / Q000494:pharmacology*; D001618:beta-Lactamases / Q000737:chemistry / Q000378:metabolism*
D004791:Enzyme Inhibitors; D013386:Succinates; C409201:beta-lactamase IMP-1; D001618:beta-Lactamases