Chemical Strategies to Modulate Intercellular Bacterial Communication

调节细胞间细菌通讯的化学策略

• 批准号: 10798787
• 负责人: Helen E. Blackwell
• 金额: $ 14.98万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798787
• 关键词: Acute Disease; Address; Advanced Development; Area; Attenuated; Award; Awareness; Bacteria; Bacterial Infections; Bacteriology; Behavior; Biochemical; Biochemistry; Biology; Cell Communication; Cell Density; Cells; Chemicals; Chemistry; Chronic Disease; Clinical; Communication; Communities; Development; Electronics; Environment; Equipment; Foundations; Genomics; Goals; Gram-Negative Bacteria; Grant; Health; Human; Individual; Infection; Intercept; Laboratories; Lead; Leadership; Ligands; Maintenance; Methods; Molecular; Organism; Outcome; Pathway interactions; Population; Positioning Attribute; Process; Receptor Signaling; Request for Proposals; Research; Research Project Grants; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; System; Testing; United States National Institutes of Health; Virulence; Vision; Work; antimicrobial; chemical synthesis; insight; intercellular communication; microbial; microbial community; microbiome; microbiota; novel therapeutic intervention; pathogen; programs; quorum sensing; receptor; small molecule; structural biology; tool

PROJECT SUMMARY/ABSTRACT This MIRA proposal outlines an integrated research program at the interface of chemistry and biology focused on cell-cell communication in bacteria, or “quorum sensing” (QS). QS has a major impact on human health, with some of the most common pathogens utilizing this sensing mechanism to regulate virulence—i.e., the ability to initiate infection—once sufficient cells have amassed to overwhelm a host. Understanding the molecular mechanisms of QS, its role in mixed microbial communities, and its impact on both acute and chronic disease remain pressing and unaddressed challenges in the field. For example, our understanding of how QS signaling molecules interact with their target protein receptors to activate or inhibit QS pathways is limited to four species in Gram-negative bacteria. Further, with an increasing awareness of the importance of microbial communities (i.e., our “microbiomes”) to human health, it is astonishing how little we know about the role of chemical signaling between these organisms in the maintenance (or disruption) of healthy microbial consortia. As bacteria use simple chemical signals to regulate QS, synthetic chemists and chemical biologists are well positioned to address these problems and other related challenges at the molecular level. With support from the NIH over the past 15 years, the PI has advanced the development of synthetic ligands that modulate QS signaling systems in Gram-negative bacteria and has shown that these ligands can strongly attenuate QS-controlled behaviors in many pathogens. This past work situates her ideally to lead this research project. The overall vision for this MIRA project is to build on the PI’s 12-year foundation of results and leadership in this area and apply a chemical approach to expand the understanding of QS across multiple scales—from individual QS signal:receptor interactions to signaling in a single species to signaling within mixed bacterial populations to interactions of the community with a host. We will achieve this vision through the pursuit of three broad Goals: (1) the development of new small molecules capable of strongly modulating QS in Gram- negative bacteria with high potencies, stabilities, and defined modes of action; (2) the application of these molecules and new chemical strategies to delineate the biochemical mechanisms of QS; and (3) characterization of the roles of QS in mixed microbial environments relevant to human health. These three Goals will be pursued through an integration of chemical synthesis, chemical biology, bacteriology, biochemistry, structural biology, and genomics. Studies will be performed in the PI’s laboratory at the UW– Madison and with a team of committed collaborators with expertise in QS and methods critical to this project. The overall outcome of this project will be a drastically increased and rigorously tested understanding of QS in bacteria and its role in biologically significant environments, and a suite of new and freely accessible research tools for the QS field. Our findings will shape the development of new methods to treat bacterial disease and will directly impact human health.

项目概要/摘要 MIRA 提案概述了化学和生物学交叉领域的综合研究计划，重点关注 细菌中的细胞间通讯，或“群体感应”（QS）。 QS对人类健康有着重大影响， 一些最常见的病原体利用这种传感机制来调节毒力，即 启动感染的能力——一旦聚集了足够的细胞来压垮宿主。了解 QS 的分子机制、其在混合微生物群落中的作用及其对急性和慢性疾病的影响 慢性病仍然是该领域紧迫且尚未解决的挑战。例如，我们的理解 QS 信号分子如何与其靶蛋白受体相互作用以激活或抑制 QS 通路 仅限于四种革兰氏阴性菌。此外，随着人们对重要性的认识不断增强 微生物群落（即我们的“微生物组”）对人类健康的影响，令人惊讶的是我们对此知之甚少 这些生物体之间的化学信号在维持（或破坏）健康微生物中的作用 财团。由于细菌使用简单的化学信号来调节 QS，合成化学家和化学生物学家 能够很好地在分子水平上解决这些问题和其他相关挑战。和 在 NIH 过去 15 年的支持下，PI 推动了合成配体的开发， 调节革兰氏阴性细菌中的 QS 信号系统，并表明这些配体可以强烈减弱 许多病原体的 QS 控制行为。过去的工作使她非常适合领导这个研究项目。 MIRA 项目的总体愿景是建立在 PI 12 年成果和领导力基础之上 并应用化学​​方法在多个尺度上扩展对 QS 的理解——从 个体 QS 信号：单一物种内信号传导与混合细菌内信号传导的受体相互作用 人群与社区与宿主的互动。我们将通过追求实现这一愿景 三大目标：（1）开发能够强烈调节革兰氏阴性菌 QS 的新小分子 具有高效力、稳定性和明确作用模式的阴性细菌； (2)这些内容的应用 描述 QS 生化机制的分子和新化学策略；和（3） 表征 QS 在与人类健康相关的混合微生物环境中的作用。这三个 将通过化学合成、化学生物学、细菌学的整合来实现目标， 生物化学、结构生物学和基因组学。研究将在 PI 位于威斯康星大学的实验室进行—— 麦迪逊和一支忠诚的合作者团队在 QS 和对该项目至关重要的方法方面拥有专业知识。 该项目的总体成果将是大幅提高对 QS 的理解并经过严格测试 细菌及其在具有重要生物学意义的环境中的作用，以及一系列可免费获取的新研究 QS 领域的工具。我们的研究结果将有助于开发治疗细菌性疾病和 将直接影响人体健康。