Enediol mimics as inhibitors of the D-arabinose 5-phosphate isomerase (KdsD) from Francisella tularensis

Bioorg Med Chem Lett. 2011 May 1;21(9):2679-82. doi: 10.1016/j.bmcl.2010.12.066. Epub 2010 Dec 19.

Abstract

We explored the D-arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Francisella tularensis, a highly infectious gram-negative pathogen that has raised concern as a potential bioweapon, as a target for the development of novel chemotherapeutics. F. tularensis KdsD was expressed in Escherichia coli from a synthetic gene, purified, and characterized. A group of hydroxamates designed to be mimics of the putative enediol intermediate in the enzyme's catalytic mechanism were prepared and tested as inhibitors of F. tularensis KdsD. The best inhibitor, which has an IC(50) of 7 μM, is the most potent KdsD inhibitor reported to date.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohols / chemical synthesis
  • Alcohols / chemistry
  • Alcohols / pharmacology*
  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / genetics
  • Aldose-Ketose Isomerases / metabolism
  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / genetics
  • Francisella tularensis / drug effects*
  • Francisella tularensis / enzymology
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Inhibitory Concentration 50
  • Molecular Structure

Substances

  • Alcohols
  • Alkenes
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Aldose-Ketose Isomerases
  • arabinose-5-phosphate isomerase