Inhibition of Mycobacterium tuberculosis topoisomerase I by m-AMSA,a eukaryotic type II topoisomerase poison |
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Authors: | Adwait Anand Godbole Wareed Ahmed Rajeshwari Subray Bhat Erin K Bradley Sean Ekins Valakunja Nagaraja |
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Institution: | 1. Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India;2. LigDCipher, 729 Nevada Ave, San Mateo, CA 94402, USA;3. Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94403, USA;4. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India |
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Abstract: | m-AMSA, an established inhibitor of eukaryotic type II topoisomerases, exerts its cidal effect by binding to the enzyme–DNA complex thus inhibiting the DNA religation step. The molecule and its analogues have been successfully used as chemotherapeutic agents against different forms of cancer. After virtual screening using a homology model of the Mycobacterium tuberculosis topoisomerase I, we identified m-AMSA as a high scoring hit. We demonstrate that m-AMSA can inhibit the DNA relaxation activity of topoisomerase I from M. tuberculosis and Mycobacterium smegmatis. In a whole cell assay, m-AMSA inhibited the growth of both the mycobacteria. |
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Keywords: | m-AMSA Type I topoisomerase Mycobacterium tuberculosis Topoisomerase inhibitors |
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