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

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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.