Suffocating tuberculosis : oxidative phosphorylation as a target space for the development of next generation anti-tuberculosis drugs

• Main Author: Lee, Bei Shi
• Other Authors: Kevin Pethe
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2022
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/155550
• Institution: Nanyang Technological University

Tuberculosis is a deadly communicable disease caused by Mycobacterium tuberculosis. Recent advances have revealed that the pathogen’s energy metabolism is particularly vulnerable to chemical inhibition. For instance, Telacebec (Q203), which targets the respiratory terminal oxidase Cyt-bcc:aa3, is highly effective in inhibiting replication. However, Q203 lacks bactericidal potency due to the compensatory effect of a second terminal oxidase, Cyt-bd. I tested the hypothesis that a Cyt-bd inhibitor could be valuable as an adjuvant to Q203. Using a representative hit, ND-011992, I showed that its combination with Q203 is lethal against replicating and non-replicating populations alike. I also investigated the role of energy metabolism in antibiotic lethality and demonstrated that respiratory inhibitors such as bedaquiline and Q203 conferred protection over the bactericidal action of isoniazid and moxifloxacin. The work here validated Cyt-bd as a valuable drug target and offers a preliminary insight of how respiratory inhibitors interact with common anti-TB drugs.