The pursuit of mechanism of action: uncovering drug complexity in TB drug discovery,RSC Chemical Biology

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The pursuit of mechanism of action: uncovering drug complexity in TB drug discovery
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-1-13 , DOI: 10.1039/d0cb00226g
Tianao Yuan ₁ , Joshua M Werman ₁ , Nicole S Sampson ₁

Affiliation

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.

中文翻译：

追寻作用机制：揭示结核病药物发现中的药物复杂性

在过去二十年中，基于全细胞的表型筛选已成为结核病 (TB) 药物发现中命中生成的主要模式。人们已经开发出不同的药物筛选模型来反映实验室结核病的复杂性。随着这些培养条件变得越来越复杂，阐明药物靶点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结核病药物之间的相互作用非常复杂，因此充分了解 MOA 对于成功提供用于结核病治疗的候选药物至关重要。没有单一的“标准”方案可供遵循，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，在药物发现领域普遍开发了多种策略，这些策略已适用于在实验室中全面表征结核病药物的 MOA。这些方法成功开发了临床前结核病候选药物，并更好地了解了结核分枝杆菌感染的发病机制。在这篇综述中，我们描述了基于遗传、代谢组学、生物化学和计算方法来研究结核病药物作用机制的大量努力。我们评估了这些不同平台在结核病药物 MOA 阐明 Mtb 发病机制方面的优势和局限性。我们强调 MOA 鉴定的重要性，概述了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。

更新日期：2021-01-13

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