The pursuit of mechanism of action: uncovering drug complexity in TB drug discovery.
The pursuit of mechanism of action: uncovering drug complexity in TB drug discovery.
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DOI：
10.1039/d0cb00226g
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发表时间：
2021-04-01
影响因子：
4.1
通讯作者：
Sampson NS
中科院分区：
文献类型：
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作者：
Yuan T;Werman JM;Sampson NS
在过去的二十年中，基于全细胞的表型筛选已经成为结核病（TB）药物发现中产生命中的主要模式。已经开发了不同的药物筛选模型，以反映实验室中结核病的复杂性。随着这些培养条件变得越来越复杂，解开药物靶标和鉴定感兴趣的化合物的作用机制（MOA）也变得更具挑战性。由于结核分枝杆菌（Mtb）与用于治疗该疾病的TB药物之间的相互作用的高度复杂性，对MOA的良好理解对于成功递送用于TB治疗的候选药物是必不可少的。没有单一的“标准”方案可以遵循，也没有单一的方法足以充分研究药物如何抑制结核分枝杆菌。然而，随着组学技术的最新进展，在药物发现领域中通常已经开发了多种策略，这些策略已经适于在实验室中全面表征TB药物的MOA。这些方法已导致临床前TB候选药物的成功开发，并更好地了解Mtb感染的发病机制。在这篇综述中，我们描述了大量的努力的基础上遗传，代谢组学，生物化学和计算方法来调查结核病药物MOAs。我们评估了这些不同平台在结核病发病机制背景下结核药物MOA阐明中的优势和局限性。通过强调MOA鉴定的重要性，我们概述了在提供结核病候选药物方面未满足的需求，并为进一步的结核病药物发现提供了方向。已成功地用于了解结核病治疗的作用机制的工具进行了讨论，以提供深入了解未来的机制评估在M。结核
Whole cell-based phenotypic screens have become the primary mode of hit generation in tuberculosis (TB) drug discovery during the last two decades. Different drug screening models have been developed to mirror the complexity of TB disease in the laboratory. As these culture conditions are becoming more and more sophisticated, unraveling the drug target and the identification of the mechanism of action (MOA) of compounds of interest have additionally become more challenging. A good understanding of MOA is essential for the successful delivery of drug candidates for TB treatment due to the high level of complexity in the interactions between Mycobacterium tuberculosis (Mtb) and the TB drug used to treat the disease. There is no single “standard” protocol to follow and no single approach that is sufficient to fully investigate how a drug restrains Mtb. However, with the recent advancements in -omics technologies, there are multiple strategies that have been developed generally in the field of drug discovery that have been adapted to comprehensively characterize the MOAs of TB drugs in the laboratory. These approaches have led to the successful development of preclinical TB drug candidates, and to a better understanding of the pathogenesis of Mtb infection. In this review, we describe a plethora of efforts based upon genetic, metabolomic, biochemical, and computational approaches to investigate TB drug MOAs. We assess these different platforms for their strengths and limitations in TB drug MOA elucidation in the context of Mtb pathogenesis. With an emphasis on the essentiality of MOA identification, we outline the unmet needs in delivering TB drug candidates and provide direction for further TB drug discovery. The tools that have been successfully employed to understand the mechanism of action of TB therapeutics are discussed to offer insights into the future of mechanistic assessment in M. tuberculosis.