Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis.
Bioenergetic Inhibitors: Antibiotic Efficacy and Mechanisms of Action in Mycobacterium tuberculosis.
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DOI：
10.3389/fcimb.2020.611683
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发表时间：
2020
影响因子：
5.7
通讯作者：
Berney M
中科院分区：
文献类型：
--
作者：
Hasenoehrl EJ;Wiggins TJ;Berney M
开发新型抗结核联合治疗方案，提高疗效，缩短治疗时间，将提高患者依从性，限制副作用，降低成本，提高治愈率。这些进展将显著改善全球结核病负担并减少耐药性的获得。近年来，生物能量学作为抗结核药物发现的一个肥沃的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，还可以杀死代谢休眠的细菌，这些细菌本身更具耐药性。在过去的二十年中，已经开发了一系列针对各种ETC组分的药物。在这里，我们提供了一个集中的审查，目前的最先进的生物能量抑制剂结核病的代谢和生物能量的干扰所造成的特定目标的抑制，以及它们与其他药物的协同和拮抗作用的深入分析。然后，这个基础是用来探索占主导地位的理论的机制，诱导细胞死亡，我们讨论如何生物能抑制剂，特别是未能充分描述这些模型。这些讨论使我们为新的研究路线制定了一个明确的路线图，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来开发新的，合理设计的联合疗法来治愈结核病。
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.
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影响因子：
4.9
作者：
Biukovic, Goran;Basak, Sandip;Grueber, Gerhard
通讯作者：
Grueber, Gerhard
影响因子：
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作者：
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van Soolingen, Dick
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Bald D;Villellas C;Lu P;Koul A
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通讯作者：
Grosset, Jacques
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4.6
作者：
Al-Attar, Sinan;Yu, Yuanjie;de Vries, Simon
通讯作者：
de Vries, Simon