Natural Product-Inspired Approaches Toward the Development of Antivirulence and Species-Specific Inhibitors

项目摘要 拟议的研究将询问天然产物支架作为抗病力的起点 和窄谱药物特别感兴趣的是减轻细菌生物膜的化合物， 是医院获得性感染的病原体，细菌耐药性的发展， 排斥医疗植入物和许多其他健康相关疾病。这些化合物， 建议将集中在，已从特权地区选择的细菌利用化学战 以防止入侵物种的定居。在这里，我们提出了一个多方面的方法，包括 有机合成、分子遗传学、蛋白质组学、转录组学和微生物测定， 从这些优越的脚手架开始，但作为一个总体目标， 治疗和工具化合物，以更好地了解多物种环境中的过程。 前两项研究的重点是寻找能抑制其中一种病毒的抗病毒化合物。 以下过程：生物膜形成、群体感应、毒力因子的产生等。 与已知的防污剂和信号分子，我们将探索独特的化学特征， 赋予每个分子生物学效应。此外，我们将利用化学工具箱， 设计具有改进的化学和物理性质的化合物，以提高 翻译.然后，将对类似物进行测试，目的是确定自然界中 产品影响并允许在一般生物膜过程中对靶标进行更广泛的评价。 第三个研究重点涉及天然产物支架的化学合成， 根际我们最近发现这些化合物具有物种特异性活性， 其对于开发“窄谱”治疗剂和工具化合物是理想的。提出 化合物来源于植物材料、内生真菌和根际细菌， 以前的生物活性。所提出的有效和简明战略的核心是 在我们先前描述的全合成中获得的知识，其提供了 模拟开发 最后的推进将研究生物靶标和工具化合物的性质， 在单一物种和多物种生物膜中。这种方法将采用遗传和 MS-蛋白质组学技术，以开发一个候选蛋白质列表，从中我们将确定目标 通过生物化学研究。以前的研究表明，这些来源提供了 具有前所未有的生物活性的化合物，对改善人类健康具有重要意义。 健康此外，它们作用于以前未知的治疗靶点， 对付细菌的方法。

Project Summary The proposed research will interrogate natural product scaffolds as starting points for antivirulence and narrow-spectrum agents. Of specific interest are compounds that mitigate bacterial biofilms, which are the causative agent in hospital-acquired infections, the development of resistance in bacteria, the rejection of medical implants, and many other health related diseases. The compounds, which this proposal will focus on, have been chosen from privileged areas where bacteria utilize chemical warfare to prevent colonization of invading species. Here we present a multi-faceted approach, including organic synthesis, molecular genetics, proteomics, transcriptomics, and microbiological assays that begins with these privileged scaffolds but has as an overarching goal of developing next generation therapeutics and tool compounds to better understand processes within a multispecies environment. The first two research thrusts seek to identify antivirulence compounds that inhibit one of the following processes: biofilm formation, quorum sensing, production of virulence factors, etc. Starting with known antifoulant and signaling molecules, we will explore the unique chemical features that endow each molecule with their biological effect. Furthermore, we will utilize the chemical toolbox to design compounds with improved chemical and physical properties to improve the likelihood of translation. Analogs will then be tested with the goal of identifying specific processes that the natural product affects and allow for a broader evaluation of the target in general biofilm processes. The third research thrust involves the chemical synthesis of natural product scaffolds identified in the rhizosphere. We have recently shown that these compounds possess species-specific activity, which is ideal for the development of “narrow-spectrum” therapeutics and tool compounds. Proposed compounds are derived from plant material, endophytic fungi, and rhizosphere bacteria and have previously demonstrated biological activity. Central to the efficient and concise strategies proposed is the knowledge gained in our previously described total syntheses which provides key intermediates for analog development. The final thrust will investigate both the biological target and properties of the tool compounds both in single species and multispecies biofilms. This approach will employ a combination of genetic and MS-proteomic techniques to develop a candidate list of proteins, from which we will identify the targets by biochemical studies. Previous research has demonstrated that these sources have provided compounds with unprecedented biological activity with significant implications to improving human health. Furthermore, they act on therapeutic targets that were previously unknown providing new approaches to combat bacteria.