Harnessing macromolecules to study microbial (bio)chemical ecology

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Overview. Bacteria are not solitary organisms: they assemble into complex communities built on extraordinary chemical landscapes that we are just beginning to understand. These microbiomes are as essential to biogeochemical cycles as they are to animal development. Due to the inherent complexity, understanding how specific collectives assemble and operate is particularly challenging. Thus, improving the approaches that provide access to the molecular details that underlie these bacterial interactions represents a major global research objective.This research proposal will develop new discovery pipelines to study small molecules by exploiting known biological systems that have evolved to facilitate chemical exchange. Bacterial small molecules from three distinct dairy cattle-associated microbiomes will be used to provide general and specific insight into bacterial community structure and function.Approach. Research projects will begin with biotechnological applications of macromolecular systems that interact with and/or transport small molecules. This approach is a departure from conventional research programs, which begin with crude and generalized extraction protocols. Instead, we will turn to the evolved roles of macromolecules to selectively enrich for ecologically important sets of small molecules. Two research pipelines will be developed. The first will leverage protein-small molecule interactions to discover and catalogue siderophores, small molecules that are involved in the acquisition of iron, an essential micronutrient. The second will survey antibiotics that have been encapsulated within outer-membrane vesicles - spherical structures - that are secreted by Gram-negative bacteria into their environment.Impact. The emphasis on evolved biological processes will afford remarkable reductions in the chemical complexity of organic extracts that are processed for chemical characterization. By simplifying our small molecule isolation pipeline, we will accelerate the rate at which new compounds are discovered and catalogue known structures to better define the chemical landscapes involved in microbial conflict and cooperation. Overall, these two pioneering studies will help to develop a new paradigm toward a molecular definition of microbiomes.In addition to the training and fundamental knowledge that will be disseminated by this research program, Canadians may also benefit from the medicinal and economic potential derived from future therapeutic applications of the newly discovered small molecules. In particular, small molecules are utilized directly or have inspired the synthesis of more than half of the drugs currently on the market. While these applied studies are beyond the scope of this proposal, we will provide foundational knowledge for future research applications.