Characterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters

Temesszentandrasi-Ambrus, Csilla and Toth, Szilard and Verma, Rinkee and Banhegyi, Peter and Szabadkai, Istvan and Baska, Ferenc and Szantai-Kis, Csaba and Hartkoorn, Ruben C and Lingerfelt, Mary A and Sarkadi, Balazs and Szakacs, Gergely and Orfi, Laszlo and Nagaraja, Valakunja and Ekins, Sean and Telbisz, Agnes (2018) Characterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters. In: PLOS ONE, 13 (9).

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Abstract

Drug resistant tuberculosis (TB) is a major worldwide health problem. In addition to the bacterial mechanisms, human drug transporters limiting the cellular accumulation and the pharmacological disposition of drugs also influence the efficacy of treatment. Mycobacterium tuberculosis topoisomerase-I (MtTopo-I) is a promising target for antimicrobial treatment. In our previous work we have identified several hit compounds targeting the MtTopo-I by in silico docking. Here we expand the scope of the compounds around three scaffolds associated with potent MtTopo-I inhibition. In addition to measuring the effect of newly generated compounds on MtTopo-I activity, we characterized the compounds' antimicrobial activity, toxicity in human cells, and interactions with human multidrug transporters. Some of the newly developed MtTopo-I inhibitors have strong antimicrobial activity and do not harm mammalian cells. Moreover, our studies revealed significant human ABC drug transporter interactions for several MtTopo-I compounds that may modify their ADME-Tox parameters and cellular effects. Promising new drug candidates may be selected based on these studies for further anti-TB drug development.

Item Type:	Journal Article
Publication:	PLOS ONE
Publisher:	PUBLIC LIBRARY SCIENCE
Additional Information:	Copy right for this article belong to PUBLIC LIBRARY SCIENCE, 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	26 Sep 2018 15:27
Last Modified:	26 Sep 2018 15:27
URI:	http://eprints.iisc.ac.in/id/eprint/60734

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