Targeting NuoD for the treatment of H. pylori

该提案旨在开发新的、更有效的、选择性的治疗螺杆菌的疗法 幽门感染慢性感染H.幽门导致消化性溃疡和胃癌。H.幽门螺杆菌是一种 重要的耐药病原体，WHO将其归类为高优先级病原体。标准 治疗包括质子泵抑制剂（PPI）和两种广谱抗生素，通常是克拉霉素 与甲硝唑或阿莫西林一起使用。这些组合越来越无效， 耐药率，并大大破坏肠道的健康微生物组。有相当多的需求没有得到满足 寻找新的、更有效的和选择性的抗生素来根除H.幽门。在我们的初步研究中，我们发现 复合物I的NuoD界面作为H.幽门。通过复合物I的反应是必不可少的 螺杆幽门螺杆菌，但不是大多数其他细菌，提供机械选择性和最大限度地减少破坏的 微生物组我们为此目标开发并验证了一个虚拟筛选平台， 使用初始抑制剂改善了药理学性质。虚拟屏幕识别的命中， 合成上易处理，具有已证实的靶向抗菌活性，以及离体和体内功效 螺旋杆菌幽门。该提案的最终目的是获得经过仔细验证的、窄谱的、口头的 生物可利用和有效的NuoD抑制剂，将形成后续临床前抗生素的基础 发展努力。这些研究也将提供对H.幽门呼吸和 抗H.幽门。

This proposal aims to develop novel, more effective, and selective therapies for the treatment of Helicobacter pylori infections. Chronic infection with H. pylori causes peptic ulcers and gastric cancer. H. pylori is an important drug-resistant pathogen, which is categorized as a high-priority pathogen by the WHO. Standard therapy consists of a proton pump inhibitor (PPI) and two broad-spectrum antibiotics, usually clarithromycin with either metronidazole or amoxicillin. These combinations are becoming increasingly ineffective with high resistance rates, and substantially disrupt the gut's healthy microbiome. There is a considerable unmet need for novel, more effective, and selective antibiotics to eradicate H. pylori. In our preliminary studies, we identified the NuoD interface of Complex I as a druggable target for H. pylori. Respiration through Complex I is essential for H. pylori, but not for most other bacteria, offering mechanistic selectivity and minimizing disruption of the microbiome. We developed and validated a virtual screening platform for this target to identify leads with improved pharmacological properties using the initial inhibitors. The virtual screen identifed hits that are synthetically tractable with demonstrated on-target antibacterial activity, and both ex vivo and in vivo efficacy against H. pylori. The ultimate aim of the proposal is to obtain carefully validated, narrow spectrum, orally bioavailable, and efficacious NuoD inhibitors that will form the basis of a subsequent preclinical antibiotic development effort. These studies will also provide a deeper understanding of H. pylori respiration and the development of selective antibiotics against H. pylori.