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

项目摘要 这项拟议的研究将询问天然产物支架作为抗病毒的起点。 和窄谱药物。特别令人感兴趣的是减少细菌生物被膜的化合物，它 是医院获得性感染的病原体，细菌耐药性的发展， 医疗植入物的排斥，以及许多其他与健康有关的疾病。这些化合物，这是 提案将集中在细菌利用化学战的特权区域 以防止入侵物种的殖民。在这里，我们介绍了一种多方面的方法，包括 有机合成、分子遗传学、蛋白质组学、转录组学和微生物分析 从这些特权脚手架开始，但将开发下一代作为首要目标 治疗学和工具化合物，以更好地了解多物种环境中的过程。 前两项研究试图确定抑制其中一种的抗毒力化合物 以下过程：生物膜形成、群体感应、毒力因子产生等。 利用已知的防污剂和信号分子，我们将探索其独特的化学特性 赋予每个分子生物效应。此外，我们将利用化学工具箱来 设计具有更好的化学和物理性能的化合物，以提高 翻译。然后将对模拟进行测试，目标是确定自然的 产品影响并允许在一般生物膜工艺中对目标进行更广泛的评估。 第三个研究重点是化学合成天然产物支架。 根际环境。我们最近表明，这些化合物具有物种特有的活性， 这是开发“窄光谱”疗法和工具化合物的理想选择。建议 化合物来自植物材料、内生真菌和根际细菌，并具有 先前已证明具有生物活性。所提出的高效而简明的策略的核心是 我们在前面描述的全合成中获得的知识为以下目的提供了关键的中间体 模拟开发。 最后的推力将调查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。这种方法将结合使用遗传和 MS-蛋白质组学技术来开发候选蛋白质列表，我们将从该列表中识别目标 通过生化研究。以前的研究已经证明，这些来源提供了 具有前所未有生物活性的化合物，对改善人类健康具有重大意义 健康。此外，它们作用于以前未知的治疗靶点，提供新的 对抗细菌的方法。

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.