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

FEMS Microbiol Lett. 2005 Feb 1;243(1):65-71. doi: 10.1016/j.femsle.2004.11.042.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects*
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Inhibitory Concentration 50
  • Kinetics
  • Meropenem
  • Microbial Sensitivity Tests
  • Succinates / chemistry
  • Succinates / pharmacology*
  • Thienamycins / pharmacology*
  • beta-Lactam Resistance / drug effects*
  • beta-Lactamase Inhibitors*
  • beta-Lactamases

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Succinates
  • Thienamycins
  • beta-Lactamase Inhibitors
  • beta-lactamase IMP-1
  • beta-Lactamases
  • Meropenem