Targeting Energy Metabolism in Mycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery.
Targeting Energy Metabolism in Mycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery.
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DOI：
10.1128/mbio.00272-17
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发表时间：
2017-04-11
期刊：
影响因子：
6.4
通讯作者：
Koul A
中科院分区：
文献类型：
--
作者：
Bald D;Villellas C;Lu P;Koul A
耐药性分枝杆菌感染是一个严重的全球健康挑战，导致全世界发展中国家的高死亡率和社会经济负担。从识别新靶点到发现新型化学支架，迫切需要新的创新方法。最近，分枝杆菌的能量代谢，特别是氧化磷酸化途径，已成为微生物研究的重点，并成为药物发现的新靶点途径。干扰氧化磷酸化途径要素的新型抗菌药物在对抗休眠或潜伏的分枝杆菌感染方面具有高度活性，有望缩短结核病化疗时间。ATP合成酶抑制剂贝达喹啉的监管批准和靶向细胞色素bc1复合物的候选药物Q203的发现，突出了这种新靶向途径的核心重要性。在这篇综述中，我们讨论了抑制能量代谢的关键特征和潜在应用，以发现有效的新型杀菌药物组合来对抗结核病。我们相信，靶向氧化磷酸化途径的药物组合可以为药物敏感和耐多药结核病带来全新的治疗方案。
Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochrome bc1 complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.