Targeting NuoD for the treatment of H. pylori

靶向 NuoD 治疗幽门螺杆菌

基本信息

批准号：
10659783
负责人：
Michael LaFleur
金额：
$ 86.55万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659783
关键词：
Amoxicillin Anti-Bacterial Agents Antibiotics Attention Bacteria Binding Binding Proteins Biochemical Biological Assay Biological Availability Carcinogens Categories Cell Membrane Permeability Cells Chemistry Chronic Clarithromycin Collection Complex Databases Development Drug Kinetics Drug resistance Epithelial Cells Feedback Galactose Genus Hippocampus Glucose Goals Growth Helicobacter Helicobacter Infections Helicobacter pylori Hepatocyte Homology Modeling Human Inflammation Ligands Liquid substance Malignant Neoplasms Measures Metronidazole Microsomes Mitochondria Modeling Monitor NADH dehydrogenase (ubiquinone)Oral Oxygen Consumption Peptic Ulcer Pharyngeal structure Phosphotransferases Property Proton Pump Inhibitors Reporting Resistance Resistance development Respiration Series Solubility Stomach Stomach Carcinoma Stress Tests Structure Testing Ulcer antagonist chronic infection combat counterscreen cytotoxicity design drug development drug resistant pathogen druggable target experimental study gastrointestinal gut microbiota improved in vitro Assay in vitro testing in vivo in vivo Model inhibitor lead candidate lead optimization malignant stomach neoplasm microbiome mutant novel novel therapeutics pathogen pathogenic bacteria pharmacologic pre-clinical priority pathogen resistant strain scaffold synergism virtual virtual screening

项目摘要

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.

该建议旨在开发新颖，更有效和选择性的疗法来治疗螺旋杆菌幽门螺杆菌感染。幽门螺杆菌的慢性感染会导致消化性溃疡和胃癌。幽门螺杆菌是重要的耐药病原体，该病原体被WHO归类为高优先性病原体。标准治疗由质子泵抑制剂（PPI）和两种广谱抗生素组成，通常是克拉霉素甲硝唑或阿莫西林。这些组合变得越来越无效，高电阻率，并实质上破坏了肠道健康的微生物组。有很大的需求对于新颖，更有效和选择性抗生素，可以消除幽门螺杆菌。在我们的初步研究中，我们确定了复合物I作为幽门螺杆菌的可药物靶标的NUOD界面。通过复杂I的呼吸是必不可少的对于幽门螺杆菌，但对于大多数其他细菌而言，没有机械选择性，并最大程度地减少了破坏的破坏微生物组。我们开发并验证了该目标的虚拟筛选平台，以识别潜在客户使用初始抑制剂改善了药理特性。虚拟屏幕标识了命中可以通过证明靶向抗菌活性的综合处理，并且在体内和体内疗效针对幽门螺杆菌。该提案的最终目的是获得精心验证的，狭窄的频谱，口服生物利用和有效的NUOD抑制剂，这些抑制剂将构成随后的临床前抗生素的基础发展工作。这些研究还将对幽门螺杆菌的呼吸和开发针对幽门螺杆菌的选择性抗生素。