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 language | English (US) |
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Pages (from-to) | S61-S65 |
Journal | Tuberculosis |
Volume | 91 |
Issue number | SUPPL. 1 |
DOIs | |
State | Published - Dec 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