Terminal oxidases as potential drug targets in mycobacteria

• Main Author: Foo, Joan Yuan Zhen
• Other Authors: Kevin Pethe
• Format: Final Year Project
• Language: English
• Published: 2016
• Subjects: DRNTU::Science
• Online Access: http://hdl.handle.net/10356/68930
• Institution: Nanyang Technological University

The main problem about tuberculosis treatment is the persistence of Mycobacterium tuberculosis despite prolonged chemotherapy. Hence, there is an urgent need to discover new drug targets to combat the dormant MDR/XDR bacilli. Nutrient-starvation triggers growth termination and renders them phenotypically drug-resistant. We conducted a series of experiments to study the feasibility of terminal oxidases i.e. cytochrome bd oxidase and cytochrome bc1-aa3 complex as potential drug targets in nutrient-starved mycobacteria by investigating the differences in energy metabolism, cell viability and drug susceptibility in nutrient-starved BCG ∆bd as compared to BCG WT and BCG ∆bd-pMV306-bd when treated with Q203, bedaquiline and INH. We concluded that combination of specific inhibitor of cytochrome bd oxidase with Q203 could have multiplicative effect against log-phase growing and dormant mycobacteria. Furthermore, potency of Q203 on nutrient-starved BCG ∆bd at low molarity was comparable to the potency of bedaquiline, suggesting Q203 as a promising clinical candidate for the treatment of tuberculosis. We also observed that reduction in energy metabolism in dormant state may be a survival strategy undertaken by the bacilli to persist in nutrient-deprived conditions and our data further validated the importance of PMF and oxidative phosphorylation pathway as potential drug targets against dormant mycobacteria.