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

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

With this award, the Chemistry of Life Processes (CLP) Program in the NSF Division of Chemistry is supporting Professor Helen Blackwell from the University of Wisconsin– Madison to investigate the chemicals that bacteria produce to communicate with each other. This communication pathway is important because many common bacteria use it to cause infections and disease in humans, animals, and plants. However, the structures of these signals and how they function remain poorly understood. The goals of this NSF project are to examine the chemical signals made by one group of bacteria, to investigate how they function in bacteria, to use chemistry to make signals that the bacteria cannot make themselves, and to apply these non-natural signals to activate and inhibit bacterial communication pathways on demand. This research approach, rooted in chemistry, allows for the signaling pathway to be explored in new ways and in important, biologically relevant environments, providing fundamental new insights into how it works. This project has additional broad impacts, which include providing ample opportunities for training students in modern scientific techniques and preparing them for advanced careers in science. In addition, immersive artwork and hands-on activities to communicate the presence of bacteria and their chemical signals in the environment, and their global importance, to the general public. This research project is motivated by the amazing ability of bacteria to act as a group at high cell number and initiate behaviors that can have devastating eQects on humanity. This process is called “quorum sensing” (QS). Gram-positive bacteria use accessory gene regulator (agr) type, two-component signaling systems for QS that are reliant on autoinducing peptide (AIP) signals. The dependence 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. In prior studies, non-native peptides were developed that are capable of either blocking or activating agr-type QS in the Staphylococci. More recently, these approaches have been extended to other pathogens and have identified some of the first small molecule inhibitors of agr-type QS. Many questions remain about the mechanisms and potential utility of these non-native compounds. The current project leverages this strong foundation of research and expands to goals that: (1) apply chemical synthesis and biosynthesis to develop next-generation ligands to target agr-type QS with improved activity profiles and physical properties; (2) apply biochemistry to delineate the molecular mechanisms by which non-native ligands interact with agr QS systems; (3) apply chemical biology to investigate the role of agr QS in mixed bacterial communities with both spatial and temporal control. Together, the results of these goals will significantly advance the current understanding of 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.