Wellington Samantha, Nag Partha P, Michalska Karolina, Johnston Stephen E, Jedrzejczak Robert P, Kaushik Virendar K, Clatworthy Anne E, Siddiqi Noman, McCarren Patrick, Bajrami Besnik, Maltseva Natalia I, Combs Senya, Fisher Stewart L, Joachimiak Andrzej, Schreiber Stuart L, Hung Deborah T
The Broad Institute, Cambridge, Massachusetts, USA.
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Nat Chem Biol. 2017 Sep;13(9):943-950. doi: 10.1038/nchembio.2420. Epub 2017 Jul 3.
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.
目前极其需要具有新型靶点的新型抗生素。细菌具有众多基本功能，但当前药物仅能抑制其中一小部分过程——主要是那些参与大分子合成的过程。靶向代谢酶已成为近期研究的热点，但难以鉴定出有效的抑制剂。我们描述了一种合成氮杂环丁烷衍生物BRD4592，它通过变构抑制色氨酸合酶（TrpAB）来杀死结核分枝杆菌（Mtb），TrpAB是一种此前未被靶向的、高度受变构调节的酶。BRD4592结合于TrpAB的α-β亚基界面，并影响该酶整体反应中的多个步骤，导致代谢环境的变化不易克服这种抑制作用。我们表明，TrpAB是Mtb和海分枝杆菌在体内存活所必需的，并且这种需求可能独立于适应性免疫反应。这项工作突出了变构抑制对于靶向天然高度动态且在体内必不可少的蛋白质的有效性，尽管这些蛋白质在体外条件下看似并非不可或缺，并且为发现下一代变构抑制剂提出了一个框架。
