Institute of Molecular and Translational Medicine, Medicinal Chemistry, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hněvotínská 5, 779 00, Olomouc, Czech Republic.
Department of Organic Chemistry, Faculty of Science, Palacky University Olomouc, 17. Listopadu 12, 771 46, Olomouc, Czech Republic.
Eur J Med Chem. 2021 Feb 15;212:113139. doi: 10.1016/j.ejmech.2020.113139. Epub 2020 Dec 29.
Causing approximately 10 million incident cases and 1.3-1.5 million deaths every year, Mycobacterium tuberculosis remains a global health problem. The risk is further exacerbated with latent tuberculosis (TB) infection, the HIV pandemic, and increasing anti-TB drug resistance. Therefore, unexplored chemical scaffolds directed towards new molecular targets are increasingly desired. In this context, mycobacterial energy metabolism, particularly the oxidative phosphorylation (OP) pathway, is gaining importance. Mycobacteria possess primary dehydrogenases to fuel electron transport; aa-type cytochrome c oxidase and bd-type menaquinol oxidase to generate a protonmotive force; and ATP synthase, which is essential for both growing mycobacteria as well as dormant mycobacteria because ATP is produced under both aerobic and hypoxic conditions. Small organic molecules targeting OP are active against latent TB as well as resistant TB strains. FDA approval of the ATP synthase inhibitor bedaquiline and the discovery of clinical candidate Q203, which both interfere with the cytochrome bc complex, have already confirmed mycobacterial energy metabolism to be a valuable anti-TB drug target. This review highlights both preferable molecular targets within mycobacterial OP and promising small organic molecules targeting OP. Progressive research in the area of mycobacterial OP revealed several highly potent anti-TB compounds with nanomolar-range MICs as low as 0.004 μM against Mtb H37Rv. Therefore, we are convinced that targeting the OP pathway can combat resistant TB and latent TB, leading to more efficient anti-TB chemotherapy.
每年导致约 1000 万例发病和 130 万至 150 万人死亡，结核分枝杆菌仍然是一个全球性的健康问题。潜伏性结核（TB）感染、HIV 大流行以及抗结核药物耐药性的增加，进一步加剧了这一风险。因此，人们越来越希望探索针对新分子靶点的未开发化学支架。在这种情况下，分枝杆菌的能量代谢，特别是氧化磷酸化（OP）途径，变得越来越重要。分枝杆菌拥有主要的脱氢酶来为电子传递提供燃料；aa 型细胞色素 c 氧化酶和 bd 型menaquinol 氧化酶来产生质子动力；以及 ATP 合酶，这对于生长中的分枝杆菌和休眠中的分枝杆菌都是必不可少的，因为在有氧和缺氧条件下都能产生 ATP。针对 OP 的小分子有机化合物对潜伏性 TB 和耐药性 TB 菌株都有活性。FDA 批准 ATP 合酶抑制剂贝达喹啉和临床候选药物 Q203 的发现，这两种药物都干扰细胞色素 bc 复合物，已经证实分枝杆菌的能量代谢是一个有价值的抗结核药物靶点。这篇综述重点介绍了分枝杆菌 OP 中的首选分子靶点以及针对 OP 的有前途的小分子有机化合物。分枝杆菌 OP 领域的研究进展揭示了几种具有纳米级范围 MIC 的高度有效的抗结核化合物，对 Mtb H37Rv 的 MIC 低至 0.004 μM。因此，我们坚信靶向 OP 途径可以对抗耐药性 TB 和潜伏性 TB，从而实现更有效的抗结核化疗。
