Novel IMP-1 metallo-β-lactamase inhibitors can reverse meropenem resistance in Escherichia coli expressing IMP-1

IMP-1 metallo-beta-lactamase is a zinc metalloenzyme that confers antibiotic resistance to bacteria through the hydrolysis of beta-lactam antibiotics. Pathogens that express the enzyme show reduced susceptibility to carbapenems, Such as meropenem and imipenem. In order to identify novel IMP-1 inhibitors, the National Cancer Institute (NCI) chemical diversity set was screened using 96-well high throughput screening format. The collection yielded several novel succinic acid derivatives that exhibited mixed inhibition of IMP-1 with compound 20707 having the highest affinity with a K-i value of 3.3 muM +/- 1.7. The compounds are moderately potent inhibitors of IMP-1 with IC50 values ranging from 5.0 to 17 muM. An original chemical class of IMP-1 inhibitor, 2-((E)-(1,3-dihydroxy-2-methylpropan-2-ylimino)methyl)-4,6-diiodophenol, was discovered and was the most potent with an IC50 of 1.2 muM. NCI compounds, 20707, 140905 and 9746 sensitized a carbapenem-resistant laboratory strain of Escherichia coli to clinically achievable levels of meropenem. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.