Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA.
School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
Nat Commun. 2019 Oct 31;10(1):4970. doi: 10.1038/s41467-019-12956-2.
The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb's respiratory chain, and highlight the challenges associated with targeting the pathogen's respiratory enzymes for tuberculosis drug development.
结核分枝杆菌（Mtb）的生存能力取决于其呼吸链产生的能量。细胞色素 bc1-aa3 氧化酶和型 2NADH 脱氢酶（NDH-2）是预测为必需的呼吸链成分，目前是药物开发的目标。在这里，我们证明了 Mtb 细胞色素 bc1-aa3 氧化酶缺失突变体在小鼠中是可行的，并且仅部分减毒。此外，用细胞色素 bc1-aa3 氧化酶抑制剂治疗感染狨猴的结核分枝杆菌可控制疾病进展并减少病变相关炎症，但大多数病变会形成空洞。删除两个 NDH-2 编码基因（Δndh-2 突变体）表明，在标准生长培养基中显示的 NDH-2 的必需性是由于脂肪酸的存在。Δndh-2 突变体在小鼠中仅轻度减毒，并且对氯法齐明（一种用于临床的拟议与 NDH-2 结合的药物）的敏感性没有差异。这些结果表明了 Mtb 呼吸链的内在可塑性，并强调了针对病原体呼吸酶进行结核病药物开发所面临的挑战。
