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品支架作为窄谱和 抗病毒剂。特别令人感兴趣的是针对特定细菌和/或缓解细菌的化合物 生物膜，它在细菌耐药性的形成、医疗植入物的排斥中发挥作用，以及 许多其他与健康有关的疾病。本提案将重点关注的化合物，是从 细菌利用化学战防止入侵物种定居的特权区域。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、 以及微生物化验，开始于这些特权的支架，但作为首要目标 开发下一代疗法和工具化合物，以更好地了解 多物种环境。 我们将询问从自然界中鉴定出的天然产品支架的化学合成 物种特异性活性，这是开发“窄光谱”疗法和工具的理想选择 化合物。建议的支架来自植物材料、真菌和根际细菌，并具有 先前已证明具有生物活性。我们建议利用分流的全合成来构建 用于生物学评价的先导化合物和假设驱动的类似物。 我们还将表征抑制生物膜形成的抗毒力化合物。从报告的自然环境开始 对于具有生物被膜抑制活性的产品，我们将探索赋予每个分子独特的化学特性 以及它们的生物效应。此外，我们还将利用化学工具箱来设计具有改进的 化学和物理性质，以提高翻译的可能性。然后，将使用 目标是确定天然产品影响的具体过程，并允许对 一般生物膜工艺中的靶标。 最后，我们将研究工具化合物的生物靶标和性质 物种和多物种生物膜。这种方法将结合遗传和MS-蛋白质组学 开发候选蛋白质列表的技术，我们将通过生物化学研究从这些列表中识别目标。 先前的研究表明，这些来源为化合物提供了前所未有的 对改善人类健康具有重大影响的生物活动。此外，它们在治疗方面起作用 以前未知的目标为抗击细菌提供了新的方法。

Project Summary The proposed research will interrogate natural product scaffolds as starting points for narrow-spectrum and antivirulence agents. Of specific interest are compounds that target specific bacteria and/or mitigate bacterial biofilms, which play a role in 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. We will interrogate the chemical synthesis of natural product scaffolds identified from nature that possess species-specific activity, which is ideal for the development of “narrow-spectrum” therapeutics and tool compounds. Proposed scaffolds are derived from plant material, fungi, and rhizosphere bacteria and have previously demonstrated biological activity. We propose to leverage diverted total synthesis to construct both the lead compound and hypothesis-driven analogs for biological evaluation. We will also characterize antivirulence compounds that inhibit biofilm formation. Starting with reported natural products with biofilm inhibitory activity, 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. Finally, we 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.