Chemical & Biological Interception of Cell-Cell Communication in Gram-Positive Bacteria

在美国国家科学基金会化学部生命过程化学(CLP)计划的支持下，威斯康星大学麦迪逊分校的海伦·E·布莱克韦尔教授正在研究细菌用来相互交流的化学信号。这一信号通路极其重要，因为许多常见细菌利用它在人类、动物和植物中引起感染和疾病。然而，人们对这些信号及其功能知之甚少。这个NSF项目旨在研究一类细菌使用的化学信号，设计和使用化学来制造细菌不能自己制造的信号，并根据需要应用这些非自然信号来激活和抑制细菌通信路径。这种化学方法将允许以新的方式和在重要的生物相关环境中探索信号通路，并将为它的工作原理提供基本的新见解。这个项目将产生额外的广泛影响。它将为学生提供大量的现代科学技术培训机会，从而为他们在科学领域的高级职业生涯做好准备。此外，通过与艺术家的合作，该项目将提供艺术品(供亲自和在线观看)，向普通公众传达细菌的存在、它们的化学信号网络以及它们在全球的重要性。这项研究项目的动机是细菌作为一个群体在高细胞数量下发挥作用并发起可能对人类产生毁灭性影响的行为的令人难以置信的能力。这个过程被称为“群体感知”(Quorum Sensation，QS)。革兰氏阳性细菌使用agr类型的两组分信号系统来实现QS，这依赖于自动诱导肽(AIP)信号。普通细菌对小肽化学语言的依赖使有机化学家和化学生物学家处于独特的地位，他们可以揭示这种交流网络背后的基本原理，并设计新的工具在分子水平上对其进行调节。布莱克韦尔教授的实验室正在为开发非天然多肽和小分子做出重要贡献，这些小分子能够阻断或激活葡萄球菌中的agr型qs。关于这些非天然化合物的机制和潜在用途，仍有许多问题需要解决。目前的项目寻求利用这一坚实的研究基础，并显著扩大PI的计划，以应对未来三年QS领域的几个关键挑战。这里将追求以下三个综合和跨学科的目标：(1)应用化学合成来开发物理上强大的下一代配体，以靶向具有改进的活性轮廓的agr型QS；(2)应用生物化学来描述这些配体与AGR QS系统相互作用的分子机制；以及(3)应用现代分子生物学来推进新的方法，以加快鉴定和生产QS配体(包括天然和非天然的)。总而言之，这些研究的结果有可能极大地完善对农业类型QS的理解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) Program in the NSF Division of Chemistry, Professor Helen E. Blackwell of the University of Wisconsin–Madison is studying the chemical signals that bacteria use to communicate with each other. This signaling pathway is extremely important, as many common bacteria use it to cause infections and disease in humans, animals, and plants. However, little is known about these signals and how they function. This NSF project aims to study the chemical signals used by one class of bacteria, to design and use chemistry to make signals that the bacteria cannot make themselves, and apply these non-natural signals to activate and inhibit bacterial communications pathways on demand. This chemical approach will allow for the signaling pathway to be explored in new ways and in important, biologically relevant environments, and will provide fundamental new insights into how it works. This project will have additional broad impacts. It will provide ample opportunities for training students in modern scientific techniques, thereby preparing them for advanced careers in science. In addition, through collaboration with an artist, the project will provide artwork (for viewing in person and online) that will communicate the presence of bacteria, their chemical signaling networks, and their global importance to the general public. This research project is motivated by the incredible ability of bacteria to act as a group at high cell number and initiate behaviors that can have devastating effects on humanity. This process is called “quorum sensing” (QS). Gram-positive bacteria use agr-type, two-component signaling systems for QS that are reliant on autoinducing peptide (AIP) signals. The reliance of common bacteria on a chemical language of small peptides places organic chemists and chemical biologists in a unique position to uncover the fundamental principles underlying this communication network and design new tools to modulate it at the molecular level. Professor Blackwell's laboratory is making important contributions to the development of non-native peptides and small molecules capable of either blocking or activating agr-type QS in the Staphylococci. Many questions remain to be addressed about the mechanisms and potential utility of these non-native compounds. The current project seeks to leverage this strong foundation of research and significantly expand the PI’s program to address several key challenges in the QS field over the next three years. The following three integrated and cross-disciplinary aims are to be pursued here: (1) apply chemical synthesis to develop physically robust, next-generation ligands to target agr-type QS with improved activity profiles; (2) apply biochemistry to delineate the molecular mechanisms by which these ligands interact with agr QS systems; and (3) apply modern molecular biology to advance new methods to expedite the identification and production of QS ligands (both native and non-native). Together, the results of these studies have the potential to significantly refine the understanding of agr-type QS.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.