School of Biological Sciences, Nanyang Technological University, 637551, Singapore.
School of Biological Sciences, Nanyang Technological University, 637551, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore.
Prog Biophys Mol Biol. 2020 May;152:45-54. doi: 10.1016/j.pbiomolbio.2020.02.001. Epub 2020 Feb 18.
Mycobacterium tuberculosis strictly depends on oxygen to multiply, and the terminal oxidases are a vital part of the oxidative phosphorylation pathway. The bacterium possesses two aerobic respiratory branches: a cytochrome bcc-aa and a bacteria-specific cytochrome bd oxidase. The identification of small-molecule inhibitors of the cytochrome bcc-aa under numerous experimental conditions reflects the essentiality of the pathway for the optimum growth of M. tuberculosis. Recent findings on the biology of the cytochrome bcc-aa as well as the report of the first high-resolution structure of a mycobacterial cytochrome bcc-aa complex will help in the characterization and further development of potent inhibitors. Although the aerobic cytochrome bd respiratory branch is not strictly essential for growth, the discovery of a strong synthetic lethal interaction with the cytochrome bcc-aa placed the cytochrome bd oxidase under the spotlight as an attractive drug target for its synergistic role in potentiating the efficacy of cytochrome bcc-aa inhibitors and other drugs targeting oxidative phosphorylation. In this review, we are discussing current knowledge about the two mycobacterial aerobic respiratory branches, their potential as drug targets, as well as potential drawbacks.
结核分枝杆菌严格依赖氧气进行繁殖，末端氧化酶是氧化磷酸化途径的重要组成部分。该细菌拥有两种需氧呼吸分支：细胞色素 bcc-aa 和细菌特异性细胞色素 bd 氧化酶。在许多实验条件下，细胞色素 bcc-aa 的小分子抑制剂的鉴定反映了该途径对结核分枝杆菌最佳生长的必要性。最近关于细胞色素 bcc-aa 生物学的发现以及第一个分枝杆菌细胞色素 bcc-aa 复合物的高分辨率结构报告将有助于对有效抑制剂进行表征和进一步开发。虽然需氧细胞色素 bd 呼吸分支对于生长不是严格必需的，但与细胞色素 bcc-aa 的强烈合成致死相互作用的发现使细胞色素 bd 氧化酶成为一个有吸引力的药物靶点，因为它在增强细胞色素 bcc-aa 抑制剂和其他针对氧化磷酸化的药物的功效方面具有协同作用。在这篇综述中，我们讨论了关于这两种分枝杆菌需氧呼吸分支的现有知识，它们作为药物靶点的潜力以及潜在的缺点。
