Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.
Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.
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DOI：
10.15252/emmm.202013207
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发表时间：
2021-01-11
影响因子：
11.1
通讯作者：
Pethe K
中科院分区：
文献类型：
--
作者：
Lee BS;Hards K;Engelhart CA;Hasenoehrl EJ;Kalia NP;Mackenzie JS;Sviriaeva E;Chong SMS;Manimekalai MSS;Koh VH;Chan J;Xu J;Alonso S;Miller MJ;Steyn AJC;Grüber G;Schnappinger D;Berney M;Cook GM;Moraski GC;Pethe K
贝达喹啉的批准使能量代谢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F1 F0 ATP合酶，但已鉴定出靶向氧化磷酸化途径其他组分的小分子。特别令人感兴趣的是Telacebec（Q203），一种细胞色素bcc：aa 3末端氧化酶的2期候选药物抑制剂。细胞色素bcc：aa 3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，突出了bd型末端氧化酶对药物开发的吸引力。在这里，我们采用了一种简单的全细胞筛选方法来鉴定细胞色素bd抑制剂ND-011992。虽然ND-011992本身无效，但与Q203联合使用时可抑制呼吸和ATP稳态。该药物组合对复制型和抗生素耐受型、非复制型分枝杆菌具有杀菌作用，并且相对于小鼠模型中的单一药物具有更高的疗效。这些发现表明，细胞色素bd氧化酶抑制剂将增加靶向氧化磷酸化治疗结核病的药物组合的价值。分枝杆菌中两种末端氧化酶的功能冗余限制了II期临床候选药物Telacebec（Q203）的疗效。在这项研究中，我们确定了一种细胞色素bd氧化酶抑制剂ND-011992，它与Q203一起形成了一种针对结核分枝杆菌的杀菌药物组合。
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 F1F0 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:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 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. The functional redundancy of two terminal oxidases in mycobacteria limits the efficacy of phase 2 clinical candidate Telacebec (Q203). In this study we identified a cytochrome bd oxidase inhibitor ND‐011992 that together with Q203 forms a bactericidal drug combination against Mycobacterium tuberculosis.