Design and Synthesis of Small-Molecule Inhibitors of Enteropathogenic Bacterial Virulence

摘要 肠道传染病仍然是一个全球性的健康问题。急性腹泻是 是全球幼儿死亡的主要原因，也是最常见的报告之一 美国的疾病。肠道疾病在缺乏足够营养的地区迅速蔓延。 卫生和饮用水，因为摄入水传播的细菌通常会导致 呕吐和腹泻，然后进一步污染转录级联 由细菌感染引发的最终导致毒力因子的表达，包括 毒素、效应分子和定殖因子。它是通过理解 细菌的毒力，我们可以了解致病因子的作用， 确定有效的治疗方法。特别是针对病毒的治疗方法 鉴于抗菌素（药物）耐药性的上升，这一点很重要。特别是，这项研究旨在利用 ToxT是一种主要的转录因子， 霍乱弧菌毒力，设计一个子集的化合物，可能作为抗毒力 剂.本研究的目标是设计和合成小分子 抑制剂（目的1），并表征其对ToxT（目的2）和其他 蛋白质的AraC/XylS超家族的成员（Aim 3）。初步数据支持我们的 假设设计模拟天然脂肪酸配体结构的化合物， ToxT在其蛋白结合构象中将导致有效的ToxT抑制。这些研究将 导致特异性靶向V的新型小分子的合成和表征。 霍乱毒力因子考虑到ToxT与其他植物中的毒力基因调节子的相似性， 细菌，拟议的研究也可能导致许多其他有效的候选药物 肠道细菌感染，包括霍乱、旅行者腹泻和痢疾。

Abstract Enteric diarrheal disease continues to be a global health concern. Acute diarrhea is a leading cause of death in young children worldwide and is one of the most commonly reported illnesses in the United States. Enteric disease spreads quickly in areas lacking adequate sanitation and drinking water, as ingestion of the waterborne bacteria commonly results in vomiting and diarrhea, and subsequently, further contamination. The transcriptional cascade initiated by bacterial infection ultimately leads to the expression of virulence factors, including toxins, effector molecules, and colonization factors. It is by understanding the mechanism of bacterial virulence that we may understand the role of virulence factors in pathogenesis and identify effective therapeutics. Virulence-specific treatment methods would be especially significant given the rise in antimicrobial (drug) resistance. In particular, this study aims to exploit the fatty acid regulatory mechanism used by ToxT, a primary transcription factor involved in Vibrio cholerae virulence, to design a subset of compounds that may act as anti-virulence agents. The goals of the proposed research are to design and synthesize small-molecule inhibitors (Aim 1) and characterize their effects on the activity of ToxT (Aim 2) and other members of the AraC/XylS superfamily of proteins (Aim 3). Preliminary data supports our hypothesis that designing compounds that mimic the structure of the natural fatty acid ligand in ToxT in its protein-bound conformation will lead to potent ToxT inhibition. These studies will result in the synthesis and characterization of novel small molecules that specifically target V. cholerae virulence factors. Given the similarity of ToxT to virulence gene regulators in other bacteria, the proposed studies could also lead to effective drug candidates for numerous other enteric bacterial infections, including cholera, travelers' diarrhea, and dysentery.