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: 10623160
• 负责人: William M Wuest
• 金额: $ 42.17万
• 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/10623160
• 关键词: Affect; Area; Bacteria; Biochemical; Biological; Biological Assay; Chemical Warfare; Chemicals; Complex; Development; Disease; Endowment; Environment; Evaluation; Genetic; Goals; Growth; Health; Human; Invaded; Lead; Methods; Microbial Biofilms; Microbiology; Molecular Genetics; Natural Products; Nature; Organic Synthesis; Plants; Process; Property; Proteins; Proteomics; Reporting; Research; Resistance development; Source; Synthesis Chemistry; Techniques; Testing; Therapeutic; Therapeutic Agents; Translations; Virulence; analog; chemical property; chemical synthesis; combat; design; fungus; improved; inhibitor; interest; medical implant; microbial community; natural product derivative; natural product inspired; 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物支架作为窄谱和 抗病毒剂特别感兴趣的是靶向特定细菌和/或减轻细菌毒性的化合物。 生物膜，在细菌耐药性的发展、医疗植入物的排斥反应中发挥作用， 许多与健康有关的疾病。本提案将重点关注的化合物选自 细菌利用化学战防止入侵物种定居的特权地区。这里我们 提出了多方面的方法，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，开始于这些特权的支架，但作为一个总体目标， 开发下一代治疗剂和工具化合物，以更好地了解 多物种环境 我们将询问化学合成的天然产物支架确定从自然界中，具有 物种特异性活性，这是开发“窄谱”疗法和工具的理想选择 化合物.提出的支架来源于植物材料、真菌和根际细菌，并且具有 以前的生物活性。我们建议利用转向全合成来构建 用于生物学评价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性化合物。从报告的自然 具有生物膜抑制活性的产品，我们将探索赋予每个分子的独特化学特征， 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合物 化学和物理性质，以提高翻译的可能性。类似物将被测试， 目标是确定天然产品影响的特定过程，并允许对天然产品进行更广泛的评估。 一般生物膜工艺中的目标。 最后，我们将研究工具化合物的生物靶点和性质， 物种和多物种生物膜。这种方法将采用遗传学和MS-蛋白质组学的组合 技术来开发一个候选蛋白质列表，我们将通过生物化学研究确定目标。 以前的研究表明，这些来源提供了前所未有的化合物， 对改善人类健康具有重大意义的生物活性。此外，它们对治疗作用 这些以前未知的目标提供了对抗细菌的新方法。