Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors

Godbole, Adwait Anand and Ahmed, Wareed and Bhat, Rajeshwari Subray and Bradley, Erin K and Ekins, Sean and Nagaraja, Valakunja (2015) Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors. In: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 59 (3). pp. 1554-1562.

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Abstract

We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and Mycobacterium tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the Mycobacterium tuberculosis and Mycobacterium smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules.

Item Type:	Journal Article
Publication:	ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Publisher:	AMER SOC MICROBIOLOGY
Additional Information:	Copy right for this article belongs to the AMER SOC MICROBIOLOGY, 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
Keywords:	DNA GYRASE; BACTERIAL CHROMOSOME; DRUG-RESISTANCE; MECHANISM; SUSCEPTIBILITY; SMEGMATIS; CLEAVAGE; ACID; FLUOROQUINOLONES; DOMAINS
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	13 May 2015 07:22
Last Modified:	25 Feb 2019 12:38
URI:	http://eprints.iisc.ac.in/id/eprint/51529

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