Chemical Strategies to Modulate Intercellular Bacterial Communication

项目摘要/摘要 这份米拉计划概述了化学和生物学交界处的综合研究计划。 细菌中的细胞间通讯，或“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感知机制来调节毒力--即 启动感染的能力-一旦积累了足够的细胞来压倒宿主。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 慢性病在这一领域仍然是紧迫和尚未解决的挑战。例如，我们对 QS信号分子如何与其靶蛋白受体相互作用激活或抑制QS通路 仅限于四种革兰氏阴性细菌。此外，随着人们越来越多地认识到 微生物群落(即我们的“微生物群”)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 处于有利地位，能够在分子水平上解决这些问题和其他相关挑战。使用 在过去的15年里，在NIH的支持下，PI推动了合成配体的发展， 调节革兰氏阴性细菌中的QS信号系统，并已表明这些配体可以强烈减弱 在许多病原体中QS控制的行为。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年来的成果和领导能力的基础上 在这一领域，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：单一物种中信号与混合细菌中信号的受体相互作用 种群与群落与宿主的相互作用。我们将通过追求以下目标实现这一愿景 三个广泛的目标：(1)开发能够强烈调节Gram中QS的新的小分子- 具有高效价、稳定性和明确作用模式的负性细菌；(2)这些细菌的应用 描述QS生化机制的分子和新的化学策略； QS在与人类健康相关的混合微生物环境中的作用表征。这三个人 目标将通过将化学合成、化学生物学、细菌学、 生物化学、结构生物学和基因组学。研究将在威斯康星大学的PI实验室进行- 麦迪逊和一支忠诚的合作者团队，他们在QS和对这个项目至关重要的方法方面具有专业知识。 该项目的总体结果将是对QS的理解大大增加并经过严格的测试 细菌及其在具有重要生物学意义的环境中的作用，以及一套新的免费获取的研究 QS领域的工具。我们的发现将塑造治疗细菌性疾病和 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.