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Elucidating the mechanism of action of octahydrobenzo[j] phenanthridinediones as novel potent antimycobacterialcompounds.

(Mtb) are in high demand. In a past FWO project (G0020.10N) we synthesized and identified the class of octahydrobenzo[j]phenanthridinediones as promising antitubercular drug candidates. Ester analogs of the compound class showed a high degree of selectivity. For these compounds, we observed a sub-μM minimal inhibitory concentration against Mtb nearly 200 times lower than the 50% cytotoxic concentration against eukaryotic cells. However, the mechanism of action andthe basis of selectivity remain unknown. Therefore, the general objective of this project is to study the mechanism of action of theoctahydrobenzo[j]phenanthridinediones. We hypothesize a selective inhibition of mycothione reductase, a unique redox pathway in Actinobacteria, as the action mechanism. To this end,(i) we will identify the proposed target through genomic analysis of spontaneous Mtb mutants.(ii) We will validate the identified target through enzymatic and cellular approaches. (iii) In addition, wewill study the activity against metabolically inactive bacilli and the synergism with existing TB drugs using state of the art models.This study will contribute to the fundamental understanding of the mechanism of action of the compound class and will add to the common knowledge on mycobacterial mycothione reductase. In the long term, the gathered knowledge could add to the development of new antitubercular drugs.
Date:1 Oct 2014  →  30 Sep 2017
Disciplines:Biochemistry and metabolism, Medical biochemistry and metabolism, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences
Project type:Collaboration project