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 metalloenzy me that efficiently hydrolyzes beta -lactam antibiotics, including carbapen ems, rendering them ineffective. Because IMP-1 has been found in several cl inically important carbapenem-resistant pathogens, there is a need for inhi bitors 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 inhibit ors of IMP-1. Determination of high resolution crystal structures and molec ular modeling of succinic acid inhibitor complexes with IMP-1 has allowed a n understanding of the potency, stereochemistry, and structure-activity rel ationships of these inhibitors.