DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

中文翻译：

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利用 DNA 编码化学文库筛选发现结核分枝杆菌 Pks13 硫酯酶活性抑制剂

DNA 编码化学库 (DEL) 技术提供了一种既省时又经济的方法，可以同时筛选数十亿种化合物，以确定它们与感兴趣的蛋白质靶标的亲和力。在此，我们报告了其用于鉴定结核分枝杆菌(Mtb ) 聚酮合酶 13 (Pks13) 硫酯酶活性的新型化学系列抑制剂。我们提出了三种化学上不同的系列抑制剂，以及它们的酶和结核分枝杆菌全细胞效力、细胞中靶点活性的测量，以及阐明它们与酶活性位点相互作用的抑制剂-酶复合物的晶体结构。其中一种抑制剂表现出良好的药代动力学特征，并在结核病 (TB) 感染的急性小鼠模型中显示出疗效。这些发现和检测方法的发展将有助于推动结核病药物的发现。