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

The National Institute of Allergy and Infectious Diseases awarded President and Fellows of Harvard College $463,375 on February 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to discover antimicrobial metabolites produced by human gut bacteria through high-throughput screening.

The research 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, then isolate and structurally characterize antimicrobial metabolites from promising candidates. The project addresses a gap in current understanding of gut microbial colonization resistance, which protects the host from pathogenic infection. While short-chain fatty acids, bile acid derivatives, and antimicrobial peptides have been identified, the researchers hypothesize that the gut microbiota produces additional bioactive compounds not yet characterized. High-throughput screening has not previously been applied to identify antimicrobial metabolites from human microbiota members.

Performance occurs in Cambridge, Massachusetts with a period of performance ending January 31, 2028. Harvard's Office For Sponsored Programs Division serves as the administrative unit for this award.

Abstract

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.