Sunday, May 18, 2025
5/18/2025
Chemical Strategies to Modulate Intercellular Bacterial Communication - PROJECT SUMMARY/ABSTRACT This MIRA proposal focuses on the remarkable ability of bacteria to switch from a single cell to a group lifestyle using simple chemical signals, a process called “quorum sensing” (QS). QS has a major impact on human health, with some of the most common pathogens utilizing this signaling mechanism to regulate virulence—i.e., the ability to initiate infection—once sufficient cells have amassed to overwhelm a host. Understanding the molecular mechanisms of QS, its role in mixed microbial communities, and its impact on both acute and chronic disease remain pressing and unaddressed challenges in the field. For example, our understanding of how QS signaling molecules interact with their target protein receptors to activate or inhibit QS pathways is limited to four species in Gram-negative bacteria. We do not know how some of the most common QS signals are transported between cells. Further, with an increasing awareness of the importance of microbial communities (i.e., our “microbiomes”) to human health, it is astonishing how little we understand about the role of chemical signaling between these organisms in the maintenance (or disruption) of healthy microbial consortia. As bacteria use small molecules to regulate QS, synthetic chemists and chemical biologists are well positioned to address these questions and other related challenges at the molecular level. With support from the NIH over the past 17+ years, the PI has advanced the development of synthetic ligands that modulate QS signaling systems in Gram-negative bacteria and has shown that these ligands can strongly attenuate QS- controlled behaviors in many pathogens. This past work situates her ideally to lead this research project. The overall vision for this MIRA project is to build on the PI’s foundation of results and leadership in this area and apply a chemical approach to expand the understanding of QS across multiple scales — from individual QS signal:receptor interactions to signaling at the singular cell level to signaling within one species and on to mixed bacterial populations. We will achieve this vision through the pursuit of three broad Goals: (1) the development of new small molecules capable of strongly modulating QS in Gram-negative bacteria with high potencies and novel modes of action; (2) the application of these molecules and new chemical strategies to delineate the biochemical mechanisms of QS; and (3) characterization QS signal localization and the roles of QS in mixed microbial communities. This project will not just turn the crank for 5 years, using our current methods. We propose a swath of new experimental approaches to explore the chemistry of QS. Studies will be performed in the PI’s laboratory at the UW–Madison and with a team of committed collaborators with expertise in microbiology, biochemistry, genetics, and materials chemistry. The outcome of this project will be a drastically increased and rigorously tested understanding of QS in bacteria and its roles in biologically relevant environments, and a suite of new and freely accessible research tools for the QS field. Our findings should shape the development of new methods to treat bacterial disease and directly impact human health.
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