Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research- Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow (Uttar Pradesh), 226301, India.
Curr Top Med Chem. 2021;21(18):1623-1643. doi: 10.2174/1568026621666210913122346.
Tuberculosis is a life-threatening disease, and the drugs discovered during the era of 1950 and 1970 are found to be inefficient due to emergent MDR and XDR-TB. Tuberculosis is difficult to treat due to the development of antibiotic resistance. ATP synthase consists of two units, F1 and F0 units. These are present in the cytoplasm and membrane of mitochondria, respectively. F1 unit comprises of a, b, and c subunit while F0 subunit has α, β, γ, δ, ε subunits. Bedaquiline was the first approved ATP synthase inhibitor in 2012 by USFDA.
Recent literature from 2005-2020 were collected using Pubmed with the keywords ATP synthase inhibitor, bedaquiline derivatives, tuberculosis. The work describing detailed analyses of bedaquiline (BDQ) was included in the current work, and others were excluded.
ATP production occurs via the ATP synthase enzyme, leading to the growth and multiplication of mycobacteria. BDQ inhibits the mycobacterium ATP synthase enzyme, a heteropolymeric complex consisting of two subunits, but it does not interfere with mammalian ATP synthase. Bedaquiline (BDQ) has become a drug of choice in treating MDR-TB and helps in reducing the treatment span. Recently observed triple mutation as wtLeu59→mtVal59; wtIle66→mtMet66 and wtGlu61→mtAsp61 of ATP synthase led to decrease BDQ binding affinity; thus, researchers are putting efforts for its newer derivative discovery.
ATP synthase inhibitor could be an alternative approach for better treatment of tuberculosis. Herein we discussed the recent advancements in the development of newer analogues of BDQ with its future perspectives.
结核病是一种危及生命的疾病，由于出现了耐多药和广泛耐药结核病，20 世纪 50 年代和 70 年代发现的药物疗效不佳。由于抗生素耐药性的发展，结核病的治疗变得困难。ATP 合酶由两个单元组成，F1 和 F0 单元。这些分别存在于细胞质和线粒体膜中。F1 单元由 a、b 和 c 亚基组成，而 F0 亚基具有 α、β、γ、δ、ε 亚基。贝达喹啉是美国食品和药物管理局（USFDA）于 2012 年批准的第一个 ATP 合酶抑制剂。
使用 Pubmed 收集了 2005 年至 2020 年的最新文献，关键词为 ATP 合酶抑制剂、贝达喹啉衍生物、结核病。本研究包括了对贝达喹啉（BDQ）进行详细分析的工作，而排除了其他工作。
ATP 通过 ATP 合酶酶产生，导致分枝杆菌的生长和繁殖。BDQ 抑制分枝杆菌的 ATP 合酶酶，该酶是一个由两个亚基组成的杂多聚体复合物，但它不干扰哺乳动物的 ATP 合酶。贝达喹啉（BDQ）已成为治疗耐多药结核病的首选药物，并有助于缩短治疗时间。最近观察到 ATP 合酶的三重突变，即 wtLeu59→mtVal59；wtIle66→mtMet66 和 wtGlu61→mtAsp61，导致 BDQ 结合亲和力降低；因此，研究人员正在努力发现其新型衍生物。
ATP 合酶抑制剂可能是治疗结核病的另一种方法。本文讨论了 BDQ 新型类似物的最新研究进展及其未来展望。
