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.
Highlights
Multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) are becoming a major worldwide health problem
Since the interaction of antituberculotic compounds with human multidrug resistance (MDR) transporters may influence general ADME-Tox properties as well as cellular drug resistance, in addition to direct MtTopo-I inhibition and bacterial growth inhibition studies we investigated the effect of these compounds on the activity of human ABCB1 and ABCG2
We suggest that compounds exhibiting significant Mtopo-I inhibition without mammalian cell toxicity and showing an advantageous ATP binding cassette (ABC) transporter interaction pattern may represent new possibilities for further anti-TB drug development
Summary
Multidrug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) are becoming a major worldwide health problem. According to the WHO database (2017), 490,000 drug resistant TB cases were identified in 2016, and an additional 110,000 cases were reported to be susceptible to isoniazid but resistant to rifampicin (RR-TB). All fundings supported experimental research aiming to find new antituberculotic compounds. Grants supported collaborative works of authors SE, RH, VN and LOin MM4TB, VN, LO , BS, GSZ in DST-TET funding, and AT in KFI_16-1-2017-0232. The funders (DST Government of India, NKFIH, Europian Community Seventh Framework Programme 7) provided supports in the form of research materials and salaries for AT. Vichem Chemie Research Ltd provided funding in the form of salaries for PB, IS, FB, CSSZ, and LO. Collaborations Pharmaceuticals Inc provided funding in the form of a salary for SE, ML. The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript
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