Department of Chemistry, Saint Mary's University, 923 Robie Street, B3H 3C3, Halifax, NS, Canada.
Department of Chemistry and Physics, Mount Saint Vincent University, 166 Bedford Highway, B3M 2J6, Halifax, NS, Canada.
ChemMedChem. 2024 Nov 18;19(22):e202400303. doi: 10.1002/cmdc.202400303. Epub 2024 Sep 20.
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.
分枝杆菌是机会性的细胞内病原体，在历史上一直困扰着人类和其他动物，直到今天仍然如此。它们操纵和劫持免疫系统的吞噬细胞，使它们能够占据这个特殊的感染位置。分枝杆菌利用大量的机制来抵抗抗生素（例如，蜡质细胞壁、外排泵、靶标修饰、生物膜等），从而进化成超级细菌，如广泛耐药结核分枝杆菌（XDR TB）杆菌和新兴的致病性脓肿分枝杆菌复合体。这篇综述总结了一些抗分枝杆菌策略的作用机制。利用分枝杆菌是严格需氧的事实，以及它们的氧化磷酸化途径与人类的差异，为药物发现开辟了一条有前途的途径。呼吸复合物在分枝杆菌病原体中的多态性给重新定位抗分枝杆菌药物以对抗非结核分枝杆菌感染的增加带来了挑战。本文还探讨了利用分枝杆菌呼吸机制数据设计新型治疗药物的计算策略。综述了分枝杆菌呼吸成分的潜在成药性。讨论了与分枝杆菌病原体相关的健康挑战的未来研究。
