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

细菌用于细胞间通讯的肽信号的化学和生物学

基本信息

批准号：
1708714
负责人：
Helen Blackwell
金额：
$ 45万
依托单位：
University of Wisconsin-Madison
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1708714&HistoricalAwards=false
关键词：
Chemistry Biology Peptide Signals Used

项目摘要

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.

通过这一奖项，NSF化学部的生命过程化学计划资助威斯康星大学麦迪逊分校的海伦·E·布莱克韦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使用的信号的化学结构，并使用获得的信息来设计和创造细菌不能自己制造的信号。这些非自然信号被用来根据需要激活和抑制细菌通讯途径。这种化学方法为细菌交流和形成对细菌信号的基本理解的生物机制提供了根本的新见解。这些项目目标的实现是为研究生提供现代实验技术方面的研究培训，为他们在科学领域的高级职业生涯做好准备。该项目的另一个主要目的是与一位知名艺术家合作，创作艺术品和身临其境的装置作品，重新想象细菌作为合作伙伴的潜力。这种媒介正被用来向美国和其他地区的广大非科学家受众传达细菌的存在、它们的化学信号网络以及它们的重要性。这项研究项目的广泛目标是表征革兰氏阳性细菌用于细胞间通信或“群体感应”(QS)的自动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。革兰氏阳性细菌的QS依赖于多肽衍生的信号，在葡萄球菌中表现最好。这些细菌使用agr类型的双组分QS信号系统，依赖于自动诱导肽(AIP)信号和同源的AGRC受体。许多与感染相关的(即毒力)表型都受agr qs系统的控制。因此，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是人们非常感兴趣的。布莱克韦尔教授的实验室最近发现了一套非天然的AIP衍生多肽，它们是AGRC受体最有效的合成抑制剂和激活剂，因此是QS。尽管AIP衍生的AGRC调节剂具有强大的效力，但它们的物理特性限制了它们作为化学工具的实用价值。此外，对于这些配体如何与AGRC受体相互作用并调节其功能，缺乏基本的机制了解。该项目通过综合使用合成化学、生化、微生物学和结构生物学方法来解决这些限制。这一期望是对目前对农业类型QS的认识的扩展。