Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-beta-lactamase.
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Toney JH, Hammond GG, Fitzgerald PM, Sharma N, Balkovec JM, Rouen GP, Olson SH, Hammond ML, Greenlee ML, Gao YD
Succinic acids as potent inhibitors of plasmid-borne IMP-1 metallo-beta-lactamase.
J Biol Chem. 2001 Aug 24;276(34):31913-8. Epub 2001 Jun 4.
- PubMed ID
- 11390410 [ View in PubMed]
- Abstract
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.