title: Inhibition of Mycobacterium tuberculosis topoisomerase I by m-AMSA, a eukaryotic type II topoisomerase poison.
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.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Adwait Anand
authors.initials: AA
authors.lastname: Godbole
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Wareed
authors.initials: W
authors.lastname: Ahmed
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Rajeshwari Subray
authors.initials: RS
authors.lastname: Bhat
authors.affiliation: LigDCipher, 729 Nevada Ave, San Mateo, CA 94402, USA.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Bradley
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94403, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India; Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India. Electronic address: vraj@mcbl.iisc.ernet.in.
authors.forename: Valakunja
authors.initials: V
authors.lastname: Nagaraja
mesh_terms: D000677:Amsacrine / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004269:DNA, Bacterial / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D004269:DNA, Bacterial; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004264:DNA Topoisomerases, Type I
keywords: Mycobacterium tuberculosis; Topoisomerase inhibitors; Type I topoisomerase; m-AMSA