Mycobacterium tuberculosis remains the most common infectious killer worldwide despite decades of antitubercular drug development. Effectively controlling the tuberculosis (TB) pandemic will require innovation in drug discovery. In this review, we provide a brief overview of the two main approaches to discovering new TB drugs—phenotypic screens and target-based drug discovery—and outline some of the limitations of each method. We then explore recent advances in genetic tools that aim to overcome some of these limitations. In particular, we highlight a novel metric to prioritize essential targets, termed vulnerability. Stratifying targets based on their vulnerability presents new opportunities for future target-based drug discovery campaigns.

中文翻译：

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薄弱环节：通过识别最脆弱的目标推进基于目标的药物发现


尽管抗结核药物已经开发了数十年，但结核分枝杆菌仍然是全世界最常见的传染病杀手。有效控制结核病（TB）大流行需要药物发现方面的创新。在这篇综述中，我们简要概述了发现新结核病药物的两种主要方法——表型筛选和基于靶标的药物发现——并概述了每种方法的一些局限性。然后，我们探索旨在克服其中一些限制的遗传工具的最新进展。我们特别强调了一种新颖的指标来优先考虑重要目标，称为脆弱性。根据目标的脆弱性对目标进行分层为未来基于目标的药物发现活动提供了新的机会。