Yuan Tianao, Werman Joshua M, Sampson Nicole S
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400, USA.
RSC Chem Biol. 2021 Apr 1;2(2):423-440. doi: 10.1039/d0cb00226g. Epub 2021 Jan 13.
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 (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.
在过去二十年中，基于全细胞的表型筛选已成为结核病药物发现中产生命中靶点的主要方式。已经开发了不同的药物筛选模型，以在实验室中反映结核病的复杂性。随着这些培养条件变得越来越复杂，阐明药物靶点以及鉴定感兴趣化合物的作用机制（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相互作用的高度复杂性，对MOA的充分理解对于成功交付结核病治疗候选药物至关重要。没有单一的“标准”方案可循，也没有一种方法足以全面研究药物如何抑制Mtb。然而，随着最近组学技术的进步，药物发现领域普遍开发了多种策略，这些策略已被应用于在实验室中全面表征结核病药物的MOA。这些方法已成功推动了临床前结核病候选药物的开发，并增进了对Mtb感染发病机制的了解。在本综述中，我们描述了基于遗传、代谢组学、生化和计算方法来研究结核病药物MOA的大量工作。我们评估了这些不同平台在阐明Mtb发病机制背景下的结核病药物MOA方面的优势和局限性。强调了MOA鉴定的必要性，我们概述了交付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。
