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

Omonike Olaleye, Tirumalai R. Raghunand, Shridhar Bhat, Curtis Chong, Peihua Gu, Jiangbing Zhou, Ying Zhang, William R. Bishai, Jun O. Liu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)S61-S65
JournalTuberculosis
Volume91
Issue numberSUPPL. 1
DOIs
StatePublished - Dec 1 2011

Keywords

  • 7-bromo-5-chloroquinolin-8-ol (CLBQ14)
  • Clioquinol (CQ)
  • Methionine aminopeptidase (MetAP)
  • Mycobacterium tuberculosis (Mtb)
  • Tuberculosis (TB)

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

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