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

• 批准号: 10029698
• 负责人: HERVE F AGAISSE
• 金额: $ 62.74万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10029698
• 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; Epithelium; 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; Preventive Intervention; 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/antagonist; medical countermeasure; microbial; pathogen; preclinical evaluation; prevent; resistant strain; scaffold; small molecule; therapeutic candidate; therapeutic lead compound

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).

抽象的 Shigella Flexneri是细菌痢疾（血腥腹泻）的主要原因，每年有1.65亿例 全球，包括100万人死亡。目前没有可用的疫苗，并且隔离多个 来自全世界患者的抗生素耐药菌株已成为常态。 S. flexneri发病机理依靠 人类结肠的定植，病原体侵入上皮细胞并直接从细胞传播到 通过基于肌动蛋白的运动性细胞。使用我们最近开发的人类志菌病的婴儿兔模型 小组，我们发现在细菌痢疾期间观察到的症状的严重程度，包括 血腥的腹泻和肠粘膜破坏与屈链球菌的效率相关 通过细胞间扩散传播。针对支持S. flexneri传播的细胞途径 因此，代表了细菌痢疾的潜在医学对策。在这里，我们建议发现 抑制S. flexneri传播的小分子（AIM 1），并根据化学和 生物分类（AIM 2）以及有限和探索性药物化学（AIM 3）。