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High Throughput Screen for Inhibitors of Shigella Flexneri Dissemination

福氏志贺氏菌传播抑制剂的高通量筛选

基本信息

批准号：
10404510
负责人：
HERVE F AGAISSE
金额：
$ 59.77万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404510
关键词：
Actins Address Affect Animal Model Antibiotic Resistance Attention Attenuated Bacteria Biological Biological Assay Biological Process Cell physiology Cells Cellular biology Cessation of life Chemicals Colon Computer-Assisted Image Analysis Cytoskeleton Cytosol Development Dose Epithelial Epithelial Cells Failure Fluorescence Microscopy Foundations Future Goals Hemorrhagic colitis Human Infant Intestinal Mucosa Intestines Invaded Laboratories Lead Libraries Membrane Modeling Oryctolagus cuniculus Parents Pathogenesis Pathway interactions Patients Pharmaceutical Chemistry Process Research Project Grants Resolution Severities Shigella Infections Shigella flexneri Symptoms Testing Therapeutic Intervention Triage Vaccines Vacuole analog base cell motility cellular targeting cytotoxicity design disorder prevention high throughput screening human model in vivo Model inhibitor medical countermeasure microbial pathogen preclinical evaluation prevent preventive intervention resistant strain scaffold small molecule therapeutic candidate therapeutic lead compound

项目摘要

Abstract Shigella flexneri is the leading cause of bacillary dysentery (bloody diarrhea) with 165 million cases per year worldwide, including 1 million deaths. There is no vaccine currently available and the isolation of multiple antibiotic resistant strains from patients worldwide is becoming the norm. S. flexneri pathogenesis relies on the colonization of the human colon where the pathogen invades epithelial cells and spreads directly from cell to cell through actin-based motility. Using an infant rabbit model of human shigellosis recently developed by our group, we have discovered that the severity of the symptoms observed during bacillary dysentery, including bloody diarrhea and destruction of the intestinal mucosa, correlates with the efficiency of S. flexneri dissemination through cell-to-cell spread. Targeting the cellular pathways supporting S. flexneri dissemination therefore represents a potential medical countermeasure for bacillary dysentery. Here, we propose to discover small molecules that inhibit S. flexneri dissemination (Aim 1) and to prioritize the hit set based on chemical and biological triage (Aim 2) and limited and exploratory medicinal chemistry (Aim 3).

摘要福氏志贺菌是细菌性痢疾（血性腹泻）的主要原因，每年有1.65亿例病例全世界，包括100万人死亡。目前没有疫苗可用，来自全世界患者的抗生素耐药菌株正在成为常态。S.弗氏病的发病机制依赖于在人类结肠的定殖中，病原体侵入上皮细胞并直接从细胞扩散到细胞通过肌动蛋白为基础的运动。本研究利用我们最近建立的人志贺氏菌病幼兔模型，组，我们发现，在细菌性痢疾期间观察到的症状的严重程度，包括出血性腹泻和肠粘膜破坏与S.福氏通过细胞间传播进行传播。靶向支持S.弗氏散布因此是细菌性痢疾的潜在医学对策。在这里，我们建议发现抑制S.福氏传播（目标1），并根据化学品和生物分类（目标2）和有限和探索性药物化学（目标3）。