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Elucidation of the octahydrobenzo[j]phenantridinediones as putitive redox cyclers in Mycobacterium tuberculosis.

Octahydrobenzo[j]phenanthridinediones (OQDs) have found to be potent antitubercular compounds with Minimal Inhibitory Concentrations (MICs) as low as 0.22 μM against both drug susceptible Mycobacterium tuberculosis (Mtb) and multi-drug resistant Mtb. Moreover, for the ester analogs we have reported a selectivity index value (CC50/MIC) of nearly 200. In the Mtb-BALB/c mice infection model, treatment of Mtb aerosol infected mice with 25 mg/kg of the lead compound reduced the bacterial load by 99%. Preliminary results have indicated that the OQDs presumably interfere with the bacillary redox homeostasis and provoke an increase in the intracellular reactive oxygen levels. The putative target for quinone analogues, according to literature, although disputed, could be mycothione reductase (Mtr). The Mtr enzyme controls the intracellular reductive environment by maintaining the low molecular thiol couple, mycothione/mycothiol, that functions as the prominent redox couple in Mtb in its reduced form. In the envisaged mechanism of action of the OQDs, the compounds act as redox cyclers with Mtr, abrogating its function. In addition, the reaction of the OQDs with Mtr results in an array of free radicals to which the bacillus ultimately succumbs. As the bacillary redox homeostasis is an unexploited target, the OQDs could be used to study the Mtr as an innovative strategy for the generation of novel mycobacteriocidal compounds.In this part of the project we want to investigate how the OQDs' activity is mediated. To this extend cell free models will be created in which the putative target is recombinant expressed and the affinity with the compounds will be confirmed. Furthermore we aim to explore the redox status within both the host cell, the macrophage, as in the bacillus itself, following exposure with the OQDs compounds. This research will greatly improve our understanding in the mechanism of action of the OQDs, the bacillary redox homeostasis and could provide the necessary proof of concept for the generation of novel anti-tubercular compounds in the long run.
Date:1 Apr 2016  →  31 Mar 2017
Disciplines:Microbiology, Systems biology, Immunology, Laboratory medicine