Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa

Eur J Med Chem. 2011 Dec;46(12):6075-82. doi: 10.1016/j.ejmech.2011.10.030. Epub 2011 Oct 21.

Abstract

There are currently no clinically useful inhibitors against metallo-β-lactamases (MBLs), enzymes that confer resistance against a broad spectrum of commonly used antibiotics and that are produced by an increasing number of bacterial pathogens. New pyrrole derivatives were synthesized and assayed for their inhibitory effect on the catalytic activity of the IMP-1 MBL from Pseudomonas aeruginosa and Klebsiella pneumoniae. Six compounds tested (3a-3c, 5, 7 and 8) show micromolar inhibition constants (K(i) values range from ∼10 to 30 μM). In silico docking was employed to investigate the binding mode of the strongest inhibitor, 3b, in the active site of IMP-1. Implications for further improvements of binding efficiency and specificity are discussed.

MeSH terms

  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Klebsiella Infections / drug therapy
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / enzymology*
  • Pseudomonas Infections / drug therapy
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / metabolism

Substances

  • Enzyme Inhibitors
  • Pyrroles
  • beta-Lactamase Inhibitors
  • beta-Lactamases