Discovery of antimicrobial metabolites from the human gut microbiota using high-throughput screening

About This Grant

Project Summary The human gut microbiota plays a critical role in health, with one of its major roles being to protect the host from microbial pathogens through a phenomenon known as colonization resistance. Effective colonization resistance is associated with increased bacterial diversity within the gut microbiota, which likely enhances the functional capabilities of the community. One microbial function thought to be important for colonization resistance is the production of antimicrobial small molecules by gut bacteria. However, our current understanding of the specific gut microbial metabolites involved in colonization resistance is limited, with identified compounds being largely restricted to previously known microbial products, including short-chain fatty acids, bile acid derivatives, and antimicrobial peptides. We hypothesize that the gut microbiota produces additional metabolites with antimicrobial activity that that are important for colonization resistance. The overall objective of this application is to discover such compounds through high-throughput screening. Specifically, we will screen a library of gut bacterial culture and supernatant extracts for growth inhibitory activity against a panel of bacterial and fungal pathogens and pathobionts relevant to the human gut microbiota (Aim 1). We will then isolate and structurally characterize antimicrobial metabolites from gut bacterial supernatants or cell pellets with promising activity (Aim 2). The proposed studies are supported by a preliminary screen demonstrating the presence of antibacterial and antifungal activity from multiple extracts in the library. To our knowledge, high-throughput screening has not been used previously to identify antimicrobial metabolites from members of the human microbiota. The proposed research therefore has high potential to identify antimicrobial compounds from these organisms, setting the stage for future efforts to understand the biological activities and roles of these metabolites within the gut microbiota, including their contributions to colonization resistance. Ultimately, our findings will provide a foundation for developing novel antimicrobial therapies and enhancing the resilience of the gut microbita against infections.