After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

中文翻译：

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结核分枝杆菌药物靶标的扩展多样性

经过数十年的相对不活跃之后，发现抗结核治疗药物的工作大量增加，使人们对结核分枝杆菌的生物学有了更深入的了解。（mtb）和有前途的新药，例如抑制ATP合酶的苯达喹啉，以及同时抑制霉菌酸合成和能量产生的硝基咪唑类delamanid和premanmanid。尽管取得了这些进展，但药物发现渠道仍然人烟稀少。该领域迫切需要具有新颖作用机制的化合物，该化合物能够抑制多重耐药性和广泛耐药性的Mtb（M / XDR-TB），并可能不复制Mtb，以期缩短所需治疗的持续时间。有关Mtb的新知识以及新的方法和技术，推动了对新目标领域的探索，例如能量产生和中央代谢，这与大分子合成中的经典目标有所不同。这里，我们回顾了作用于这些新颖靶标的新的小分子药物候选物，以突出推进该领域的方法和观点。这些新的目标带来了缩短治疗时间的愿望，以及一系列针对XDR-TB的有效疗法，使Mtb药物发现成为抗感染发现的模型。