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

点击翻译按钮获取中文摘要

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.