Open AccessCharacterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters
Author(s) -
Csilla Temesszentandrási-Ambrus,
Szilárd Tóth,
Rinkee Verma,
Péter Bánhegyi,
István Szabadkai,
Ferenc Baska,
Csaba Szántai-Kis,
Ruben C. Hartkoorn,
Mary A. Lingerfelt,
Balázs Sarkadi,
Gergely Szakács,
László Őrfi,
Valakunja Nagaraja,
Sean Ekins,
Ágnes Telbisz
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0202749
Subject(s) - atp binding cassette transporter , mycobacterium tuberculosis , multiple drug resistance , tuberculosis , microbiology and biotechnology , topoisomerase , transporter , biology , drug resistance , medicine , dna , genetics , gene , pathology
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.