Development of novel anti-tuberculosis combination regimens that increase efficacy and reduce treatment timelines will improve patient compliance, limit side-effects, reduce costs, and enhance cure rates. Such advancements would significantly improve the global TB burden and reduce drug resistance acquisition. Bioenergetics has received considerable attention in recent years as a fertile area for anti-tuberculosis drug discovery. Targeting the electron transport chain (ETC) and oxidative phosphorylation machinery promises not only to kill growing cells but also metabolically dormant bacilli that are inherently more drug tolerant. Over the last two decades, a broad array of drugs targeting various ETC components have been developed. Here, we provide a focused review of the current state of art of bioenergetic inhibitors of Mtb with an in-depth analysis of the metabolic and bioenergetic disruptions caused by specific target inhibition as well as their synergistic and antagonistic interactions with other drugs. This foundation is then used to explore the reigning theories on the mechanisms of antibiotic-induced cell death and we discuss how bioenergetic inhibitors in particular fail to be adequately described by these models. These discussions lead us to develop a clear roadmap for new lines of investigation to better understand the mechanisms of action of these drugs with complex mechanisms as well as how to leverage that knowledge for the development of novel, rationally-designed combination therapies to cure TB.

开发可提高疗效并缩短治疗时间的新型抗结核联合方案将提高患者依从性、限制副作用、降低成本并提高治愈率。这些进步将显着改善全球结核病负担并减少耐药性的获得。近年来，生物能学作为抗结核药物发现的肥沃领域受到了相当大的关注。靶向电子传递链 (ETC) 和氧化磷酸化机制不仅可以杀死生长中的细胞，还可以杀死本来就更具耐药性的代谢休眠杆菌。在过去的 20 年中，已经开发出一系列针对各种 ETC 成分的药物。在这里，我们重点回顾了生物能抑制剂的当前技术水平山地车对特定靶点抑制引起的代谢和生物能破坏以及它们与其他药物的协同和拮抗相互作用进行了深入分析。然后，这个基础被用来探索抗生素诱导细胞死亡机制的主导理论，我们讨论了生物能抑制剂如何无法被这些模型充分描述。这些讨论引导我们为新的研究路线制定清晰的路线图，以更好地了解这些具有复杂机制的药物的作用机制，以及如何利用这些知识开发新型、合理设计的联合疗法来治愈结核病。