title: Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis.
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.
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. olaleyeoa@tsu.edu
authors: Omonike
authors: O
authors: Olaleye
authors: Tirumalai R
authors: TR
authors: Raghunand
authors: Shridhar
authors: S
authors: Bhat
authors: Curtis
authors: C
authors: Chong
authors: Peihua
authors: P
authors: Gu
authors: Jiangbing
authors: J
authors: Zhou
authors: Ying
authors: Y
authors: Zhang
authors: William R
authors: WR
authors: Bishai
authors: Jun O
authors: JO
authors: Liu
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007464:Clioquinol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D063208:Methionyl Aminopeptidases; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011480:Protease Inhibitors; D007464:Clioquinol; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases