Chemical Strategies to Modulate Intercellular Bacterial Communication

项目总结/摘要 这MIRA建议概述了一个综合的研究计划，在化学和生物学的接口集中 细菌中细胞间的通讯，或称“群体感应”（QS）。QS对人类健康有重大影响， 一些最常见的病原体利用这种传感机制来调节毒力-即，的 一旦有足够的细胞聚集起来压倒宿主，就有能力开始感染。了解 QS的分子机制，它在混合微生物群落中的作用，以及它对急性和 慢性病仍然是该领域尚未解决的紧迫挑战。例如，我们对 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途径， 仅限于革兰氏阴性菌中的四种。此外，随着人们越来越认识到 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 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 在分子水平上能够很好地解决这些问题和其他相关挑战。与 在过去15年中，PI在NIH的支持下，推进了合成配体的开发， 调节革兰氏阴性菌中的QS信号传导系统，并已表明这些配体可强烈减弱 许多病原体的QS控制行为。过去的工作使她成为领导这项研究项目的理想人选。 这个MIRA项目的总体愿景是建立在PI 12年的成果和领导基础上 在这一领域，并应用化学方法，以扩大跨多个尺度的QS的理解-从 单个QS信号：受体相互作用到单个物种中的信号到混合细菌内的信号 群体与宿主的相互作用。我们将通过追求以下目标来实现这一愿景： 三个广泛的目标：（1）开发能够强烈调节革兰氏中QS的新的小分子， 具有高效力、稳定性和确定的作用模式的阴性细菌;（2）这些的应用 分子和新的化学策略，以描绘QS的生化机制;和（3） QS在与人类健康相关的混合微生物环境中的作用的表征。这三 目标将通过化学合成，化学生物学，细菌学， 生物化学、结构生物学和基因组学。研究将在UW的PI实验室进行- 麦迪逊和一个团队的承诺合作者的专业知识，在质量和方法的关键，这个项目。 该项目的总体成果将是对QS的理解得到大幅提高和严格测试， 细菌及其在生物重要环境中的作用，以及一套新的和免费获得的研究 QS领域的工具。我们的发现将有助于开发治疗细菌性疾病的新方法， 将直接影响人类健康。

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.