TY - JOUR
T1 - Characterization of clioquinol and analogues as novel inhibitors of methionine aminopeptidases from Mycobacterium tuberculosis
AU - Olaleye, Omonike
AU - Raghunand, Tirumalai R.
AU - Bhat, Shridhar
AU - Chong, Curtis
AU - Gu, Peihua
AU - Zhou, Jiangbing
AU - Zhang, Ying
AU - Bishai, William R.
AU - Liu, Jun O.
N1 - Funding Information:
This work was supported in part by NIH AI36973, AI37856, AI43846, and AI30036. O.O was supported by the UNCF*Merck Graduate Science Research Dissertation Fellowship and National Aeronautics Space Administration (NASA)-Harriett Jenkins Pre-doctoral Fellowship.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - 7-bromo-5-chloroquinolin-8-ol (CLBQ14)
KW - Clioquinol (CQ)
KW - Methionine aminopeptidase (MetAP)
KW - Mycobacterium tuberculosis (Mtb)
KW - Tuberculosis (TB)
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U2 - 10.1016/j.tube.2011.10.012
DO - 10.1016/j.tube.2011.10.012
M3 - Article
C2 - 22115541
AN - SCOPUS:84655163390
VL - 91
SP - S61-S65
JO - Bulletin of the International Union Against Tuberculosis and Lung Disease
JF - Bulletin of the International Union Against Tuberculosis and Lung Disease
SN - 1472-9792
IS - SUPPL. 1
ER -