Inhibition of Mycobacterium tuberculosis topoisomerase I by m-AMSA, a eukaryotic type II topoisomerase poison

Biochem Biophys Res Commun. 2014 Apr 18;446(4):916-20. doi: 10.1016/j.bbrc.2014.03.029. Epub 2014 Mar 15.

Abstract

m-AMSA, an established inhibitor of eukaryotic type II topoisomerases, exerts its cidal effect by binding to the enzyme-DNA complex thus inhibiting the DNA religation step. The molecule and its analogues have been successfully used as chemotherapeutic agents against different forms of cancer. After virtual screening using a homology model of the Mycobacterium tuberculosis topoisomerase I, we identified m-AMSA as a high scoring hit. We demonstrate that m-AMSA can inhibit the DNA relaxation activity of topoisomerase I from M. tuberculosis and Mycobacterium smegmatis. In a whole cell assay, m-AMSA inhibited the growth of both the mycobacteria.

Keywords: Mycobacterium tuberculosis; Topoisomerase inhibitors; Type I topoisomerase; m-AMSA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amsacrine / chemistry
  • Amsacrine / pharmacology*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • DNA Topoisomerases, Type I / metabolism*
  • DNA, Bacterial / metabolism
  • Humans
  • Molecular Docking Simulation
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / enzymology
  • Mycobacterium smegmatis / growth & development
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / growth & development
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology*
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*
  • Tuberculosis / drug therapy
  • Tuberculosis / microbiology

Substances

  • Antitubercular Agents
  • DNA, Bacterial
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Amsacrine
  • DNA Topoisomerases, Type I