High Throughput Screen for Inhibitors of Shigella Flexneri Dissemination

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）。

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).