The EAGER award will explore a new strategy for studying the chemical reactions taking place within complex microbial communities (microbiomes): the development of drug-like small molecules that will selectively inhibit specific microbial metabolic activities occurring in these habitats. Microorganisms living in microbiomes carry out chemical transformations (metabolism) that enable their growth and survival, mediate interactions with other organisms, and influence the health of surrounding environments. Despite the importance of these chemical processes, the details of how they affect microbiome stability and function are not yet understood, in part because organisms in communities cannot be manipulated using genetics. Access to small molecules that perturb individual reactions would transform microbiome research by enabling scientists across different disciplines to manipulate specific microbial activities in a complex community setting and observe the consequences for the community and surrounding environments and organisms. These tools would be generally applicable across multiple types of microbial communities, and they could benefit society in numerous ways: altering the human microbiome to prevent or treat disease; adjusting plant microbiomes to provide improved crop productivity or protection from pathogens; and modulating soil microbiomes to prevent metabolic activities that generate greenhouse gases. Finally, this project will offer a unique, interdisciplinary training opportunity for young scientists by exposing them to research at the interface of chemical biology and microbiology.
A major obstacle in microbiome research is elucidating how individual microbial metabolic activities shape these assemblages and affect their interactions with other organisms. The long-term goal of this project is to develop a set of small molecule inhibitors that may be used by the microbiome research community as transformative tools for manipulating specific microbial functions in vivo. The proposed approach for identifying initial lead inhibitors relies on in vivo high-throughput screens using differential growth-based assays. This strategy should rapidly reveal molecules that inhibit bacterial utilization of specific growth substrates. Importantly, this screening paradigm requires that inhibitors are efficacious in the context of a diverse set of target organisms from the outset. Incorporating this stringent criterion will ensure hits can be quickly progressed to innovative tool compounds that selectively alter specific microbial activities in vivo, providing information about their roles in shaping communities, microbe-microbe interactions, and host biology. This EAGER proposal will focus on the execution of an initial high-throughput screen to uncover inhibitors of anaerobic bacterial choline utilization, as well as the development of growth-based assays targeting additional microbial metabolic activities.
