Chemistry and Biology of the Peptide Signals Used by Bacteria for Cell-Cell Communication

美国国家科学基金会化学部的生命过程化学项目正在资助来自威斯康辛大学麦迪逊分校的海伦·e·布莱克威尔博士，研究细菌用来相互交流的化学信号。这种交流途径很重要，因为许多常见的细菌利用它来引发人类、动物和植物的感染。该项目旨在研究一类细菌所使用的信号的化学结构，并利用所获得的信息来设计和制造细菌自身无法制造的信号。这些非自然信号被用来根据需要激活和抑制细菌的通信途径。这种化学方法为细菌交流的生物学机制提供了新的见解，并形成了对细菌信号传导的基本理解。这些项目目标的实现是为研究生提供现代实验技术的研究训练，为他们在科学领域的高级职业生涯做好准备。这个项目的另一个主要推动力是，与一位知名艺术家合作，创造艺术品和沉浸式装置作品，其中细菌作为合作伙伴的潜力被重新想象。这种媒介被用于传播细菌的存在，它们的化学信号网络，以及它们对美国和其他地区的广大非科学家受众的重要性。本研究项目的主要目标是表征革兰氏阳性菌用于细胞间通讯或“群体感应”（QS）的自诱导肽的化学和生物学特性，并利用这些发现开发新的化学工具。革兰氏阳性菌的QS依赖于肽来源的信号，在葡萄球菌物种中得到最好的表征。这些细菌使用agr型双组分信号系统进行QS，该系统依赖于自诱导肽（AIP）信号和同源AgrC受体。许多感染相关的表型（即毒力）都在agr QS系统的控制之下。因此，人们对开发化学和生物策略来调节agr型QS信号，从而减弱这些病原体的影响非常感兴趣。Blackwell教授的实验室最近发现了一组非天然的aip衍生肽，它们是AgrC受体最有效的合成抑制剂和激活剂，因此也是QS的激活剂。尽管它们的效力，aip衍生的AgrC调节剂具有物理特性，限制了它们作为化学工具的效用。此外，对这些配体如何与AgrC受体相互作用并调节其功能缺乏基本的机制理解。该项目通过综合使用合成化学、生物化学、微生物学和结构生物学方法来解决这些限制。期望是对agr型QS当前知识的扩展。

With this award, the Chemistry of Life Processes Program in the NSF's Chemistry Division is funding Dr. Helen E. Blackwell from the University of Wisconsin-Madison to investigate the chemical signals that bacteria use to communicate with each other. This communication pathway is important, as many common bacteria use it to initiate infections in humans, animals, and plants. This project aims to study the chemical structures of the signals used by one class of bacteria and use the obtained information to design and create signals that the bacteria cannot make themselves. These non-natural signals are used to activate and inhibit bacterial communications pathways on demand. Such a chemical approach provides fundamental new insights into the biological mechanisms by which bacteria communicate and shape basic understanding of bacterial signaling. Realization of these project goals is providing research training for graduate students in modern experimental techniques, preparing them for advanced careers in science. Another major thrust of this project is, in collaboration with an established artist, creating artwork and an immersive installation piece where the potential of bacteria to act as cooperative partners is re-imagined. This medium is being used in communicating the presence of bacteria, their chemical signaling networks, and their importance to a broad non-scientist audience in the USA and beyond. The broad goals of this research project are to characterize the chemistry and biology of the autoinducing peptides used by Gram-positive bacteria for cell-cell communication, or "quorum sensing" (QS), and to exploit these findings for the development of new chemical tools. QS in Gram-positive bacteria depends on peptide-derived signals and is best characterized in staphylococcal species. These bacteria use agr-type, two-component signaling systems for QS that are reliant on autoinducing peptide (AIP) signals and cognate AgrC receptors. Many infection-related (i.e., virulence) phenotypes are under the control of the agr QS system. Accordingly, there is significant interest in the development of chemical and biological strategies to modulate agr-type QS signaling and thereby attenuate the impact of these pathogens. Professor Blackwell's laboratory recently discovered a suite of non-native, AIP-derived peptides that are the most potent synthetic inhibitors and activators of AgrC receptors, and thereby QS. Despite their potency, AIP-derived AgrC modulators possess physical qualities that limit their utility as chemical tools. Further, there is a lack of basic mechanistic understanding of how these ligands interact with AgrC receptors and modulate their function. This project addresses these limitations with the integrated use of synthetic chemical, biochemical, microbiological and structural biological approaches. The expectation is an expansion in the current knowledge of agr-type QS.