Targeting Mycobacterium tuberculosis topoisomerase I by small-molecule inhibitors

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 sme...

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Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2015-03, Vol.59 (3), p.1549-1557
Main Authors: Godbole, Adwait Anand, Ahmed, Wareed, Bhat, Rajeshwari Subray, Bradley, Erin K, Ekins, Sean, Nagaraja, Valakunja
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Bacterial Proteins
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - metabolism
Binding Sites - genetics
DNA - genetics
DNA Topoisomerases, Type I
DNA Topoisomerases, Type I - metabolism
DNA, Bacterial - genetics
Experimental Therapeutics
Imipramine - pharmacology
Mutation - genetics
Mycobacterium smegmatis
Mycobacterium smegmatis - drug effects
Mycobacterium smegmatis - genetics
Mycobacterium smegmatis - metabolism
Mycobacterium tuberculosis
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - metabolism
Small Molecule Libraries
Small Molecule Libraries - pharmacology
Topoisomerase I Inhibitors
Topoisomerase I Inhibitors - pharmacology
Tuberculosis - drug therapy
Tuberculosis - microbiology
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Summary: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 M. 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 M. tuberculosis and M. 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.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.04516-14