Global dispersion of multidrug resistant bacteria is very common and evolution of antibiotic-resistance is occurring at an alarming rate, presenting a formidable challenge for humanity. The development of new therapeuthics with novel molecular targets is urgently needed. Current drugs primarily affect protein, nucleic acid, and cell wall synthesis. Metabolic pathways, including those involved in amino acid biosynthesis, have recently sparked interest in the drug discovery community as potential reservoirs of such novel targets. Tryptophan biosynthesis, utilized by bacteria but absent in humans, represents one of the currently studied processes with a therapeutic focus. It has been shown that tryptophan synthase (TrpAB) is required for survival of Mycobacterium tuberculosis in macrophages and for evading host defense, and therefore is a promising drug target. Here we present crystal structures of TrpAB with two allosteric inhibitors of M. tuberculosis tryptophan synthase that belong to sulfolane and indole-5-sulfonamide chemical scaffolds. We compare our results with previously reported structural and biochemical studies of another, azetidine-containing M. tuberculosis tryptophan synthase inhibitor. This work shows how structurally distinct ligands can occupy the same allosteric site and make specific interactions. It also highlights the potential benefit of targeting more variable allosteric sites of important metabolic enzymes.

中文翻译：

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结核分枝杆菌色氨酸合酶的变构抑制剂。


多重耐药细菌在全球范围内扩散非常普遍，抗生素耐药性的进化正以惊人的速度发生，给人类带来了巨大的挑战。迫切需要开发具有新分子靶点的新疗法。目前的药物主要影响蛋白质、核酸和细胞壁的合成。代谢途径，包括参与氨基酸生物合成的代谢途径，最近引起了药物发现界的兴趣，作为此类新靶标的潜在储存库。色氨酸生物合成由细菌利用，但在人类中不存在，代表了目前以治疗为重点的研究过程之一。研究表明，色氨酸合酶（TrpAB）是结核分枝杆菌在巨噬细胞中生存和逃避宿主防御所必需的，因此是一个有前途的药物靶点。在这里，我们展示了 TrpAB 的晶体结构，以及属于环丁砜和吲哚-5-磺酰胺化学支架的两种结核分枝杆菌色氨酸合酶变构抑制剂。我们将我们的结果与之前报道的另一种含有氮杂环丁烷的结核分枝杆菌色氨酸合酶抑制剂的结构和生化研究进行了比较。这项工作展示了结构不同的配体如何占据相同的变构位点并产生特定的相互作用。它还强调了针对重要代谢酶的更多可变变构位点的潜在好处。