Novel IMP-1 metallo-beta-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 Ki value of 3.3 microM+/-1.7. The compounds are moderately potent inhibitors of IMP-1 with IC50 values ranging from 5.0 to 17 microM. 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 microM. NCI compounds, 20707, 140905 and 9746 sensitized a carbapenem-resistant laboratory strain of Escherichia coli to clinically achievable levels of meropenem.
Moloughney
Joseph G
JG
Department of Chemistry and Biochemistry, Montclair State University, 1 Normal Avenue, Montclair, NJ 07043, USA.
D Thomas
Janice
J
Toney
Jeffrey H
JH
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D020128:Inhibitory Concentration 50; D007700:Kinetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology*; D013845:Thienamycins / Q000494:pharmacology*; D018440:beta-Lactam Resistance / Q000187:drug effects*; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013386:Succinates; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; C409201:beta-lactamase IMP-1; D001618:beta-Lactamases; D000077731:Meropenem