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A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2017-07-03 00:00:00 , DOI: 10.1038/nchembio.2420
Samantha Wellington , Partha P Nag , Karolina Michalska , Stephen E Johnston , Robert P Jedrzejczak , Virendar K Kaushik , Anne E Clatworthy , Noman Siddiqi , Patrick McCarren , Besnik Bajrami , Natalia I Maltseva , Senya Combs , Stewart L Fisher , Andrzej Joachimiak , Stuart L Schreiber , Deborah T Hung

New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes—primarily those involved in macromolecular synthesis—are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB α–β-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.

中文翻译:

一种结核分枝杆菌色氨酸合酶的小分子变构抑制剂

迫切需要具有新靶标的新型抗生素。细菌具有许多基本功能,但是目前这种药物只能抑制一小部分这样的过程,主要是参与大分子合成的过程。靶向代谢酶已成为近期关注的焦点,但是有效的抑制剂一直难以鉴定。我们描述了合成的氮杂环丁烷衍生物BRD4592,它通过色氨酸合酶(TrpAB)的变构抑制作用杀死结核分枝杆菌(Mtb),色氨酸合酶是以前未靶向的,高度变构调节的酶。BRD4592结合在TrpAB α-β-亚基界面,影响酶的整体反应的多个步骤,导致代谢环境变化不易克服的抑制作用。我们表明,TrpAB是体内Mtb和海洋分枝杆菌的生存所必需的,并且该需求可能独立于适应性免疫应答。这项工作强调了变构抑制作用对天然高动态且在体内必不可少的蛋白质的靶向作用,尽管它们在体外条件下具有明显的可分散性,并为发现下一代变构抑制剂提供了框架。
更新日期:2017-08-19
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