Discovery of streptococcal natural products with activity against the endodontic pathogen Enterococcus faecalis

/Summary Bacteria in the oral cavity contribute to human health and disease. Streptococcus mutans is commonly found in the oral microbiome and is recognized as a leading cause of caries (cavities). Some infections in the oral cavity can also occur after endodontic treatments such as root canals. Millions of patients undergo root canal procedures each year, and root canal failure rates can be as high as ~20%. A leading cause of infected root canals is the Gram-positive bacterium Enterococcus faecalis, which is found at low abundance in the gastrointestinal tracts (GIT) of humans, animals, and insects. E. faecalis can also be an opportunistic pathogen causing infections on implanted devices and in body sites such as the urinary tract, bloodstream, and wounds. Despite its prevalence in root canal infections, E. faecalis is not typically considered part of the core oral microbiome. Our preliminary data shows that natural products (such as non-ribosomal peptides/polyketides) synthesized by S. mutans can kill E. faecalis and other Gram-positive bacteria. Through this proposal, we will identify natural products with anti-bacterial and anti-biofilm activity produced by additional strains of S. mutans using a combination of targeted gene deletions, bacterial co-culture assays, and mass spectrometry. Additionally, we will test the hypothesis that S. mutans biofilms producing these natural products can exclude E. faecalis from invading pre-formed biofilms and can shape biofilm dynamics in conditions relevant to the oral cavity. This work will serve as the foundation for a future R01 to NIDCR to test models of colonization resistance and dysbiosis that may govern E. faecalis dynamics in the oral cavity, and to determine how streptococcal natural products shape the ecology of the oral microbiome. Project Number: 1R03DE034751-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Julia Willett | Institution: UNIVERSITY OF MINNESOTA, MINNEAPOLIS, MN | Award Amount: $310,000 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZDE1 TO (04)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11116625