Screening of LOPAC®1280 drug library to identify inhibitors of oxidative phosphorylation in mycobacterium bovis

• Main Author: Ang, Jing Wen
• Other Authors: Kevin Pethe
• Format: Final Year Project
• Language: English
• Published: 2017
• Subjects: DRNTU::Science
• Online Access: http://hdl.handle.net/10356/71750
• Institution: Nanyang Technological University

The major challenge of tuberculosis control lies in the increased prevalence of emerging drug resistance strains and the ability of mycobacteria to persist under intense environmental stress. Therefore, there is an urgent need for the discovery of compounds with novel actions against the heterogeneous population of mycobacteria. The oxidative phosphorylation pathway has been identified as a promising target due to its essentially for survival in both dormant and replicative mycobacteria. Compound21, which is an experimental drug synthesized by Garrett C. Moraski from Montana State University, was found to be such a drug which inhibits the cytochrome bd oxidase. Based on the characteristics of the drug, compound21 was found to deplete intracellular ATP content of nutrient-starved mycobacteria in the presence of Q203. However, despite the ability to enhance the potency of Q203 action in replicative mycobacteria, the compound showed no activity on growth inhibition alone. In this study, the potency of Q203 was validated to be shifted from bacteriostatic to bactericidal upon the genetic deletion of the cytochrome bd oxidase. Four pharmacologically active drug compounds were also identified from the screening of the LOPAC®1280 library as potential cytochrome bd inhibitor which displayed similar action as compound21 with Q203.