Kinetic characterization of a slow-binding inhibitor of Bla2: thiomaltol

J Enzyme Inhib Med Chem. 2013 Feb;28(1):137-42. doi: 10.3109/14756366.2011.640632. Epub 2012 Jan 11.

Abstract

The increasing prevalence of drug resistant bacteria is a pandemic problem. Metallo-β-lactamases (MBLs) are one of the main causes of drug resistance due to hydrolysis of β-lactam antibiotics. Thus, the development of effective inhibitors of MBLs remains urgent. The compound thiomaltol was used as a lead compound to investigate its ability to inhibit metallo-β-lactamase from Bacillus anthracis (Bla2), which causes anthrax. Kinetic evaluation with nitrocefin as a substrate indicates that thiomaltol inhibits Bla2 in a time-dependent manner with an IC(50) value of 290 µM after 20 min preincubation. Progress curve analysis and reversibility tests suggest that thiomaltol is a reversible, slow-binding inhibitor with a K(i) of 85 ± 30 µM. Furthermore, studies on the modality of inhibition and in silico analysis indicate thiomaltol to be a competitive inhibitor. The results demonstrate that thiomaltol is a promising lead compound for slow binding inhibitor design of Bla2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacillus anthracis / enzymology*
  • Cephalosporins / metabolism
  • Computer Simulation
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyrans / chemistry
  • Pyrans / pharmacology*
  • Thiones / chemistry
  • Thiones / pharmacology*
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / metabolism

Substances

  • 3-hydroxy-2-methyl-4H-pyran-4-thione
  • Anti-Bacterial Agents
  • Cephalosporins
  • Enzyme Inhibitors
  • Pyrans
  • Thiones
  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • nitrocefin