Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Medical Biophysics, The University of Toronto, Toronto, Ontario, Canada.
Nature. 2021 Jan;589(7840):143-147. doi: 10.1038/s41586-020-3004-3. Epub 2020 Dec 9.
Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis. This drug can sterilize even latent M. tuberculosis infections and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Bedaquiline targets the mycobacterial ATP synthase, which is an essential enzyme in the obligate aerobic Mycobacterium genus, but how it binds the intact enzyme is unknown. Here we determined cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in complex with bedaquiline. The drug-free structure suggests that hook-like extensions from the α-subunits prevent the enzyme from running in reverse, inhibiting ATP hydrolysis and preserving energy in hypoxic conditions. Bedaquiline binding induces large conformational changes in the ATP synthase, creating tight binding pockets at the interface of subunits a and c that explain the potency of this drug as an antibiotic for tuberculosis.
结核病是全球由传染病导致的头号死因，其对现有一线抗生素的耐药性日益增强。结核分枝杆菌（导致结核病的细菌）能够在低能量条件下存活，从而使感染处于潜伏状态，并降低其对许多抗生素的敏感性。贝达喹啉于 2005 年从对耻垢分枝杆菌的表型筛选中确定的先导化合物开发而来。这种药物甚至可以使潜伏性结核分枝杆菌感染得到灭菌，并已成为治疗耐多药和广泛耐药结核病的基石。贝达喹啉靶向分枝杆菌的 ATP 合酶，这是需氧分枝杆菌属中的一种必需酶，但它如何结合完整的酶尚不清楚。在这里，我们确定了耻垢分枝杆菌 ATP 合酶单独存在和与贝达喹啉结合的冷冻电子显微镜结构。无药物结构表明，来自α亚基的钩状延伸阻止了酶的反向运行，抑制了 ATP 水解，并在缺氧条件下保存了能量。贝达喹啉结合诱导 ATP 合酶发生大的构象变化，在亚基 a 和 c 的界面处形成紧密的结合口袋，这解释了这种药物作为结核病抗生素的效力。
