Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis

Tuberculosis (Edinb). 2011 Dec:91 Suppl 1:S61-5. doi: 10.1016/j.tube.2011.10.012. Epub 2011 Nov 23.

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis claims about five thousand lives daily world-wide, while one-third of the world is infected with dormant tuberculosis. The increased emergence of multi- and extensively drug-resistant strains of M. tuberculosis (Mtb) has heightened the need for novel antimycobacterial agents. Here, we report the discovery of 7-bromo-5-chloroquinolin-8-ol (CLBQ14)-a congener of clioquinol (CQ) as a potent and selective inhibitor of two methionine aminopeptidases (MetAP) from M. tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. N-terminal methionine excision (NME) is a universally conserved process required for the post-translational modification of a significant part of the proteome. The essential role of MetAP in microbes makes it a promising target for the development of new therapeutics. Using a target-based approach in a high-throughput screen, we identified CLBQ14 as a novel MtMetAP inhibitor with higher specificity for both MtMetAP1s relative to their human counterparts. We also found that CLBQ14 is potent against replicating and aged non-growing Mtb at low micro molar concentrations. Furthermore, we observed that the antimycobacterial activity of this pharmacophore correlates well with in vitro enzymatic inhibitory activity. Together, these results revealed a new mode of action of clioquinol and its congeners and validated the therapeutic potential of this pharmacophore for TB chemotherapy.

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

  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / metabolism
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / pharmacology*
  • Clioquinol / administration & dosage
  • Clioquinol / analogs & derivatives
  • Clioquinol / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Methionyl Aminopeptidases
  • Microbial Sensitivity Tests / methods
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / growth & development
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / pharmacology*

Substances

  • Antitubercular Agents
  • Protease Inhibitors
  • Clioquinol
  • Aminopeptidases
  • Methionyl Aminopeptidases