School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
EMBO Mol Med. 2021 Jan 11;13(1):e13207. doi: 10.15252/emmm.202013207. Epub 2020 Dec 7.
The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F F ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa terminal oxidase. A functional redundancy between the cytochrome bcc:aa and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic-tolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.
贝达喹啉的批准将能量代谢置于聚光灯下，成为结核病抗生素开发的一个有吸引力的目标空间。虽然贝达喹啉抑制分枝杆菌 F F ATP 合酶，但已经确定了针对氧化磷酸化途径其他成分的小分子。特别引人关注的是 Telacebec（Q203），这是一种处于 2 期临床试验阶段的候选药物，可抑制细胞色素 bcc:aa 末端氧化酶。细胞色素 bcc:aa 和细胞色素 bd 氧化酶之间的功能冗余保护结核分枝杆菌免受 Q203 诱导的死亡，这凸显了 bd 型末端氧化酶在药物开发方面的吸引力。在这里，我们采用了一种简便的全细胞筛选方法来鉴定细胞色素 bd 抑制剂 ND-011992。尽管 ND-011992本身无效，但它与 Q203 联合使用可抑制呼吸和 ATP 稳态。该药物组合对复制和抗生素耐药、非复制分枝杆菌具有杀菌作用，并且在小鼠模型中相对于单一药物的疗效增加。这些发现表明，细胞色素 bd 氧化酶抑制剂将为针对氧化磷酸化的结核病治疗药物组合增添价值。
