New β-phospholactam as a carbapenem transition state analog: Synthesis of a broad-spectrum inhibitor of metallo-β-lactamases

Bioorg Med Chem Lett. 2013 Nov 1;23(21):5855-9. doi: 10.1016/j.bmcl.2013.08.098. Epub 2013 Sep 8.

Abstract

In an effort to test whether a transition state analog is an inhibitor of the metallo-β-lactamases, a phospholactam analog of carbapenem has been synthesized and characterized. The phospholactam 1 proved to be a weak, time-dependent inhibitor of IMP-1 (70%), CcrA (70%), L1 (70%), NDM-1 (53%), and Bla2 (94%) at an inhibitor concentration of 100μM. The phospholactam 1 activated ImiS and BcII at the same concentration. Docking studies were used to explain binding and to offer suggestions for modifications to the phospholactam scaffold to improve binding affinities.

Keywords: Inhibitor; Metallo-β-lactamase; Phospholactam.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Carbapenems / chemistry*
  • Carbapenems / pharmacology*
  • Humans
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / enzymology*
  • Molecular Docking Simulation
  • Phosphorylation
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Carbapenems
  • beta-Lactamase Inhibitors
  • beta-Lactamases