Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling.

Area of Science:

• Microbiology
• Pathogen Biology
• Drug Discovery

Background:

• Mycobacteria are opportunistic intracellular pathogens causing historical and current human/animal infections.
• They evade immune cells and possess antimicrobial resistance mechanisms (e.g., waxy cell walls, efflux pumps, biofilms).
• This leads to superbugs like extensively drug-resistant tuberculosis (XDR TB) and Mycobacterium abscessus complex.

Purpose of the Study:

• To review emerging antimycobacterial strategies and their mechanisms of action.
• To explore novel drug discovery avenues targeting mycobacterial unique pathways.
• To discuss challenges and future directions in combating mycobacterial infections.

Main Methods:

• Review of current literature on antimycobacterial strategies.
• Analysis of mycobacterial physiology, focusing on aerobic respiration and oxidative phosphorylation.
• Discussion of in silico approaches for therapeutic agent design.
• Evaluation of the druggability of mycobacterial respiratory elements.

Main Results:

• Mycobacteria's obligate aerobic nature and distinct oxidative phosphorylation pathways offer drug targets.
• Polymorphism in respiratory complexes presents challenges for drug repositioning against nontuberculous mycobacterial infections.
• In silico strategies show promise for designing novel antimycobacterial agents.

Conclusions:

• Targeting mycobacterial respiratory pathways is a promising strategy for developing new antimicrobials.
• Overcoming challenges related to pathogen polymorphism is crucial for effective treatment.
• Further research into mycobacterial respiratory elements is essential for addressing global health challenges posed by these pathogens.