Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis

Guzman, J.D., Gupta, A., Evangelopoulos, D., Basavannacharya, C., Pabon, L.C., Plazas, E.A., Munoz, D.R., Delgado, W.A., Cuca, L.E., Ribon, W., Gibbons, S. and Bhakta, S. (2010) Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis. Journal of Antimicrobial Chemotherapy, 65 (10). pp. 2101-2107. 10.1093/jac/dkq313.

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DOI: 10.1093/jac/dkq313

Abstract

Objectives: New anti-mycobacterial entities with novel mechanisms of action are clinically needed for treating resistant forms of tuberculosis. The purpose of this study was to evaluate anti-tubercular activity and selectivity of seven recently isolated natural products from Colombian plants. Methods: MICs were determined using a liquid medium growth inhibition assay for Mycobacterium tuberculosis H37Rv and both solid and liquid media growth inhibition assays for Mycobacterium bovis BCG. Escherichia coli growth inhibition and mammalian macrophage cell toxicity were evaluated to establish the degree of selectivity of the natural product against whole cell organisms. Enzymatic inhibition of ATP-dependent MurE ligase from M. tuberculosis was assayed using a colorimetric phosphate detection method. The most active compound, 3-methoxynordomesticine hydrochloride, was further investigated on M. bovis BCG for its inhibition of sigmoidal growth, acid-fast staining and viability counting analysis. Results: Aporphine alkaloids were found to be potent inhibitors of slow-growing mycobacterial pathogens showing favourable selectivity and cytotoxicity. In terms of their endogenous action, the aporphine alkaloids were found inhibitory to M. tuberculosis ATP-dependent MurE ligase at micromolar concentrations. A significantly low MIC was detected for 3-methoxynordomesticine hydrochloride against both M. bovis BCG and M. tuberculosis H37Rv. Conclusions: Considering all the data, 3-methoxynordomesticine hydrochloride was found to be a potent anti-tubercular compound with a favourable specificity profile. The alkaloid showed MurE inhibition and is considered an initial hit for exploring related chemical space.

Item Type:Article
Uncontrolled Keywords:Aporphine alkaloids; MurE inhibitors; TB
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:3063
Journal or Publication Title:Journal of Antimicrobial Chemotherapy
Deposited By:Library Staff
Deposited On:23 Mar 2012 12:21
Last Modified:23 Mar 2012 12:21

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