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

Temesszentandrási-Ambrus, Csilla and Tóth, Szilárd and Verma, Rinkee and Bánhegyi, Péter and Szabadkai, István and Sarkadi, Balázs and Szakács, Gergely and Őrfi, László and Telbisz, Ágnes Mária (2018) Characterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters. PLOS ONE, 13 (9). ISSN 1932-6203

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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: Article
Uncontrolled Keywords: ARTICLE; CYTOTOXICITY; human; drug distribution; multidrug resistance protein 1; breast cancer resistance protein; controlled study; nonhuman; drug effect; verapamil; enzyme activity; enzyme inhibition; DRUG DESIGN; human cell; drug metabolism; unclassified drug; drug protein binding; drug structure; drug inhibition; Quercetin; enzyme inhibitor; ANTIMICROBIAL ACTIVITY; Mycobacterium tuberculosis; drug absorption; cell transport; Clomipramine; drug excretion; mammal cell; adenosine triphosphatase; Molecular docking; DNA topoisomerase inhibitor; ABC transporter subfamily B; 1,2,3,4,6,7,12,12a octahydro 6 isobutyl 9 methoxy 1,4 dioxopyrazino[1',2':1,6]pyrido[3,4 b]indole 3 propanoic acid tert butyl ester; compound 340963; compound 389777; compound 450327; compound 450822; compound 478498; compound 891909; compound 979812; reversin 121;
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3015 Molecular biology / molekuláris biológia
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 06 Mar 2019 10:54
Last Modified: 06 Mar 2019 10:54
URI: http://real.mtak.hu/id/eprint/91800

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