Harikishore Amaravadhi, Grüber Gerhard
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Antibiotics (Basel). 2024 Dec 3;13(12):1169. doi: 10.3390/antibiotics13121169.
() infection causes tuberculosis (TB). TB is one of the most intractable infectious diseases, causing over 1.13 million deaths annually. Under harsh growing conditions, the innate response of mycobacteria is to shut down its respiratory metabolism to a basal level, transit into a dormant, non-replicating phase to preserve viability, and establish latent infection. utilizes non-canonical regulatory mechanisms, such as alternative oxidase pathways, to survive in low oxygen/nutrient conditions. The bacterium's survival in its native microenvironmental niches is aided by its ability to evolve mutations to drug binding sites, enhance overexpression of various enzymes that activate β-lactam antibiotics hydrolysis, or stimulate efflux pathways to ward off the effect of antibiotics. Bedaquiline and its 3,5-dialkoxypyridine analogs, sudapyridine and squaramide S31f, have been shown to be potent FF-ATP synthase inhibitors of replicating and non-replicating and have brought oxidative phosphorylation into focus as an anti-TB target. In this review, we attempt to highlight non-canonical structural and regulatory pathogen-specific epitopes of the F-domain, ligand development on such sites, structural classes of inhibitors targeting the Fo-domain, and alternative respiratory metabolic responses that employs in response to bedaquiline to ensure its survival and establish latent infection.
（）感染会引发结核病（TB）。结核病是最难治疗的传染病之一，每年导致超过113万人死亡。在恶劣的生长条件下，分枝杆菌的固有反应是将其呼吸代谢降至基础水平，进入休眠、非复制阶段以维持生存能力，并建立潜伏感染。利用非经典调控机制，如交替氧化酶途径，在低氧/营养条件下存活。该细菌在其天然微环境生态位中的存活得益于其在药物结合位点发生突变、增强激活β-内酰胺抗生素水解的各种酶的过表达或刺激外排途径以抵御抗生素作用的能力。贝达喹啉及其3,5-二烷氧基吡啶类似物、苏达吡啶和方酸酰胺S31f已被证明是复制型和非复制型的有效FF-ATP合酶抑制剂，并使氧化磷酸化成为抗结核靶点。在本综述中，我们试图强调F结构域的非经典结构和调控病原体特异性表位、此类位点上的配体开发、靶向Fo结构域的抑制剂的结构类别，以及为确保其存活和建立潜伏感染而对贝达喹啉做出反应时所采用的替代呼吸代谢反应。
