Oxidative phosphorylation as a drug target space in mycobacteria

• Main Author: Low, Samuel Xin Zher
• Other Authors: Kevin Pethe
• Format: Final Year Project
• Language: English
• Published: 2016
• Subjects: DRNTU::Science
• Online Access: http://hdl.handle.net/10356/68281
• Institution: Nanyang Technological University

The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) and latent TB infection has emphasised the need to identify novel drug targets which are capable of eliminating both drug resistant, and dormant Mtb. The recognition of energy metabolism as an essential pathway for survival in all forms of Mtb had led to a strong interest in targeting various components of the respiratory chain. Recent attempts to identify compounds that target ATP synthesis and PMF generation have yielded agents such as bedaquiline and Q203 which are found to be highly efficacious respiratory inhibitors. While current respiratory inhibitors mainly target essential components of the respiratory chain, studies of the cytochrome bd, the non-essential mycobacterial respiratory branch have revealed it as a potential drug target, given its confirmed roles in adaptation against oxidative and antibiotic stress. In this study, we showed that the genetic inactivation of cytochrome bd enhances the susceptibility of M. bovis to the respiratory inhibitors, Q203 & Lansoprazole sulfide. In addition, it was demonstrated that Q203 and Bedaquiline can elicit delayed bactericidal activity in a time-dependent manner.