High Throughput Screen for Inhibitors of Shigella Flexneri Dissemination

摘要 福氏志贺氏菌是细菌性痢疾（血性腹泻）的主要原因，每年有 1.65 亿例病例 全球范围内，包括 100 万人死亡。目前尚无可用的疫苗，并且需要隔离多种病毒 全世界患者的抗生素耐药菌株正在成为常态。福氏链球菌的发病机制依赖于 人类结肠定植，病原体侵入上皮细胞并直接从细胞传播到 细胞通过基于肌动蛋白的运动。使用我们最近开发的人类志贺氏菌病幼兔模型 小组，我们发现细菌性痢疾期间观察到的症状的严重程度，包括 血性腹泻和肠粘膜破坏，与福氏链霉菌的功效相关 通过细胞间传播进行传播。靶向支持福氏链霉菌传播的细胞途径 因此代表了细菌性痢疾的潜在医学对策。在这里，我们建议发现 抑制弗氏链球菌传播（目标 1）的小分子，并根据化学和 生物分类（目标 2）和有限和探索性药物化学（目标 3）。

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).