California Institute for Biomedical Research, La Jolla, CA, 92037, USA.
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Angew Chem Int Ed Engl. 2018 Mar 19;57(13):3478-3482. doi: 10.1002/anie.201800260. Epub 2018 Feb 22.
The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high-throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb. Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 nm against Mtb. Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh-2 enzymes in Mtb, which will allow precise control over Ndh-2 function in Mtb to facilitate the assessment of this anti-TB drug target.
通过氧化磷酸化产生 ATP 是结核分枝杆菌（Mtb）的基本代谢功能，无论其生长环境如何。Ⅱ型 NADH 脱氢酶（Ndh-2）是电子进入该途径的通道，而在哺乳动物基因组中不存在，因此它是一个潜在的药物靶点。在此，我们通过多组分高通量筛选报告了两种类型的小分子作为 Ndh-2 的选择性抑制剂。这两种化合物都能阻断 ATP 的合成，导致与 NADH 周转率丧失一致的效果，重要的是，对 Mtb 具有杀菌活性。广泛的药物化学优化提供了最佳类似物，对 Mtb 的 MIC 为 90nm。此外，这两种支架对 Mtb 中两种同源 Ndh-2 酶具有不同的抑制活性，这将允许对 Mtb 中 Ndh-2 功能进行精确控制，以促进对这种抗结核药物靶点的评估。
