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 signali