Natural Product-Inspired Approaches Toward The Development Of Antivirulence And Species-Specific Inhibitors

受天然产物启发的抗病毒和物种特异性抑制剂开发方法

• 批准号: 10619866
• 负责人: William M Wuest
• 金额: $ 5.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619866
• 关键词: Affect; Area; Bacteria; Biochemical; Biological; Biological Assay; Chemical Warfare; Chemicals; Complex; Development; Disease; Environment; Evaluation; Genetic; Goals; Growth; Health; Human; Invaded; Lead; Light; Methods; Microbial Biofilms; Microbiology; Molecular Genetics; Natural Products; Nature; Organic Synthesis; Plants; Play; Process; Property; Proteins; Proteomics; Reporting; Research; Resistance development; Role; Source; Synthesis Chemistry; Techniques; Testing; Therapeutic; Therapeutic Agents; Translations; analog; chemical property; chemical synthesis; combat; design; fungus; improved; inhibitor; interest; medical implant; microbial community; novel; novel strategies; novel therapeutics; pathogenic bacteria; physical property; polymicrobial biofilm; prevent; scaffold; therapeutic target; tool; transcriptomics

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.

项目摘要 拟议的研究将询问天然产品脚手架，作为狭窄光谱和的起点 抗动力剂。特定感兴趣的是靶向特定细菌和/或减轻细菌的化合物 生物膜在细菌的抗药性发展中发挥作用 许多其他与健康有关的疾病。该提案将重点关注的化合物是从中选择的 细菌利用化学战来防止入侵物种定殖的特权地区。我们在这里 提出了一种多面方法，包括有机合成，分子遗传学，保护性，转录组学， 以及从这些特权脚手架开始的微生物学测定，但作为总体目标 开发下一代疗法和工具化合物，以更好地了解 多人环境。 我们将询问从拥有的自然中鉴定出的自然产物支架的化学合成 规格特定的活动，这是开发“狭窄光谱”疗法和工具的理想选择 化合物。提出的脚手架源自植物材料，真菌和根际细菌，具有 以前证明了生物学活性。我们建议利用转移的总合成来构建 用于生物学评估的铅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防病毒化合物。从报告的天然开始 具有生物膜抑制活性的产品，我们将探索每个分子的独特化学特征 具有生物学效应。此外，我们将利用化学工具箱来设计改进的化合物 化学和物理特性以提高翻译的可能性。然后将使用类似物测试 确定天然产品影响并允许更广泛评估的特定过程的目标 一般生物膜过程中的目标。 最后，我们将在单一中研究工具化合物的生物靶标和性能 物种和多物种生物膜。这种方法将采用遗传和MS-蛋白质组的组合 开发蛋白质候选清单的技术，我们将通过生化研究确定靶标。 先前的研究表明，这些来源为前所未有的化合物提供了 生物活性对改善人类健康具有重要意义。此外，他们采取了治疗 以前未知的靶标提供了对抗细菌的新方法。