Anti-tubercular screening of natural products from Colombian plants: 3-methoxynordomesticine, an inhibitor of MurE ligase of Mycobacterium tuberculosis.
OBJECTIVE
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 H(37)Rv 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 H(37)Rv.


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.
Guzman
Juan D
JD
Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, UK.
Gupta
Antima
A
Evangelopoulos
Dimitrios
D
Basavannacharya
Chandrakala
C
Pabon
Ludy C
LC
Plazas
Erika A
EA
Muñoz
Diego R
DR
Delgado
Wilman A
WA
Cuca
Luis E
LE
Ribon
Wellman
W
Gibbons
Simon
S
Bhakta
Sanjib
S
D000995:Antitubercular Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001688:Biological Products / Q000494:pharmacology*; D003105:Colombia; D003124:Colorimetry / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008025:Ligases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000494:pharmacology*; D010944:Plants / Q000737:chemistry
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001688:Biological Products; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D008025:Ligases; D010453:Peptide Synthases; C554750:MurE protein, Mycobacterium tuberculosis