Tuberculosis (TB), the leading cause of death by infectious disease worldwide, is increasingly resistant to first line antibiotics. Developed from a screen against Mycobacterium smegmatis, bedaquiline can sterilize even latent M. tuberculosis infections that may otherwise persist for decades and has become a cornerstone of treatment for multidrug resistant and extensively-drug resistant TB. Bedaquiline targets mycobacterial ATP synthase, an essential enzyme in the obligate aerobic Mycobacterium genus. However, how the drug binds the intact enzyme is unknown. We determined the structure of M. smegmatis ATP synthase with and without bedaquiline. The drug-free structure reveals hook-like extensions from the enzyme's α subunits that inhibit ATP hydrolysis in low-energy conditions, such as during latent infections. Bedaquiline binding induces global conformational changes in ATP synthase, creating tight binding pockets at the interface of subunits a and c. These binding sites explain the drug's structure-activity relationship and its potency as an antibiotic for TB.

中文翻译：

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分枝杆菌苯达喹啉与分枝杆菌ATP合酶的结构

结核病（TB）是全球传染病致死的首要原因，对一线抗生素的耐药性日益增强。贝达喹啉是从针对耻垢分枝杆菌的筛选中开发出来的，甚至可以对潜伏的结核分枝杆菌感染进行灭菌，否则这种感染可能会持续数十年，并已成为耐多药和广泛耐药结核病治疗的基石。贝达喹啉靶向分枝杆菌ATP合酶，这是专性需氧分枝杆菌属中的必需酶。但是，该药物如何结合完整酶尚不清楚。我们确定了有和没有苯达喹啉的耻垢分枝杆菌ATP合酶的结构。无药结构揭示了酶α亚基的钩状延伸，在低能条件下（例如在潜伏感染期间）抑制ATP水解。Bedaquiline结合诱导ATP合酶的整体构象变化，在亚基a和c的界面上产生紧密的结合口袋。这些结合位点解释了该药物的结构-活性关系及其作为结核病抗生素的效力。