Inhibition of IMP-1 Metallo-Beta-Lactamase and Sensitization of IMP-1-producing Bacteria by Thioester Derivatives

FEMS Microbiol Lett. 1999 Oct 15;179(2):289-96. doi: 10.1111/j.1574-6968.1999.tb08740.x.

Abstract

IMP-1 metallo-beta-lactamase is a transferable carbapenem-hydrolyzing enzyme found in some clinical isolates of Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae. Bacteria that express IMP-1 show significantly reduced sensitivity to carbapenems and other beta-lactam antibiotics. A series of thioester derivatives has been shown to competitively inhibit purified IMP-1. As substrates for IMP-1, the thioesters yielded thiol hydrolysis products which themselves were reversible competitive inhibitors. The thioesters also increased sensitivity to the carbapenem L-742,728 in an IMP-1-producing laboratory stain of Escherichia coli, but will need further modification to improve their activity in less permeable organisms such as Pseudomonas and Serratia. Nonetheless, the thioester IMP-1 inhibitors offer an encouraging start to overcoming metallo-beta-lactamase-mediated resistance in bacteria.

MeSH terms

  • Bacteria / drug effects*
  • Bacteria / enzymology
  • Carbapenems / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Sulfhydryl Compounds / pharmacology*
  • beta-Lactamase Inhibitors*

Substances

  • Carbapenems
  • Enzyme Inhibitors
  • Sulfhydryl Compounds
  • beta-Lactamase Inhibitors