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

• Published in: ChemMedChem 2024-11, Vol.19 (22), p.e202400303-n/a
• Main Authors: Matar, Islam K., Dong, Zhongmin, Matta, Chérif F.
• Format: Article
• Language: English
• Subjects: Aerobes; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antimicrobial agents; Antimycobacterial agents; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Biofilms; Cell walls; computational drug discovery; Drug development; Efflux; Hansen's disease (leprosy); Humans; Immune system; Microbial Sensitivity Tests; Models, Molecular; Molecular modelling; Molecular Structure; mycobacterial oxidative phosphorylation; Mycobacterium - drug effects; Mycobacterium - metabolism; NTM pulmonary disease; Opportunist infection; Oxidation resistance; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Pathogens; Phagocytes; Pharmacology; Phosphorylation; Polymorphism; Review; Tuberculosis
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202400303

Mycobacteria are opportunistic intracellular pathogens that have plagued humans and other animals throughout history and still are today. They manipulate and hijack phagocytic cells of immune systems, enabling them to occupy this peculiar infection niche. Mycobacteria exploit a plethora of mechanisms to resist antimicrobials (e. g., waxy cell walls, efflux pumps, target modification, biofilms, etc.) thereby evolving into superbugs, such as extensively drug‐resistant tuberculosis (XDR TB) bacilli and the emerging pathogenic Mycobacterium abscessus complex. This review summarizes the mechanisms of action of some of the surging antimycobacterial strategies. Exploiting the fact that mycobacteria are obligate aerobes and the differences between their oxidative phosphorylation pathways versus their human counterpart opens a promising avenue for drug discovery. The polymorphism of respiratory complexes across mycobacterial pathogens imposes challenges on the repositioning of antimycobacterial agents to battle the rise in nontuberculous mycobacterial infections. In silico strategies exploiting mycobacterial respiratory machinery data to design novel therapeutic agents are touched upon. The potential druggability of mycobacterial respiratory elements is reviewed. Future research addressing the health challenges associated with mycobacterial pathogens is discussed. Intracellular pathogens are exceedingly clinically challenging, including pathogenic mycobacteria. Many global efforts are currently in action to battle these notorious disease agents. This review provides an overview of mycobacteria, along with their associated diseases, pathogenesis, and exploitable respiratory vulnerabilities to supplement contemporary antimycobacterial discovery.