Structures and functions of natural products in periodontal disease

The oral microbiome plays a crucial role in maintaining oral health and our overall well-being. Dysbiosis in this community drives diseases such as dental caries and periodontitis, which are respectively associated with the pathogens Streptococcus mutans and Porphyromonas gingivalis. Most Americans will be affected by periodontal disease in their lifetime, and severe periodontitis is linked to systemic health issues including atherosclerosis, arthritis, and neurological disorders. While periodontitis can be treated with physical plaque removal and broad- spectrum antibiotics, these drugs exacerbate dysbiosis by harming beneficial bacteria, increasing the risk of recurrent resistant infection. New strategies are now needed to prevent and selectively treat periodontal disease while preserving healthy oral microbiomes. Leads for pathogen-specific antibiotics can surprisingly be found from within the human microbiome, where Enterobacteriaceae like E. coli use small molecule natural products known as microcins to selectively kill related, competing strains. Microbial natural products also play a role in the oral microbiome, where antibacterial molecules from commensal and pathogenic Streptococci influence infection and colonization resistance, providing chemical leads for the selective treatment of dental caries. In this proposal, we seek to broaden this paradigm and investigate the role of microbial natural products in periodontal disease. Our efforts center on a novel natural product biosynthetic gene cluster (BGC) found in clinical isolates of P. gingivalis, which appears to encode an antibiotic selective for other P. gingivalis strains and related Bacteriodales oral pathogens. In Aim 1 of this proposal, we will create genetic knockouts and transcriptional reporters to identify conditions for the expression of this pathway. We will use these tools to investigate whether this BGC supports antibiotic-mediated antagonism of P. gingivalis and related bacteria from the oral microbiome. In Aim 2, we will use bioinformatic predictions, enzymatic assays, comparative metabolomics, and solid phase peptide synthesis to access this first natural product from Porphyromonas, enabling bioactivity tests. Based on genetic predictions, we expect this molecule will exploit a novel target to selectively eliminate bacteria associated with periodontal disease. Overall, this research will describe a molecule used by P. gingivalis to antagonize related microbes, providing a biological strategy and chemical lead for the development of targeted antibiotics that can selectively treat periodontal disease while preserving healthy oral microbiomes. Beyond the direct impact of this work on the selective treatment of periodontitis, we expect this molecule to illuminate a new strategy for Gram negative specific antibiotics that can eliminate increasingly resistant pathogens and limit further incentives for resistance. Project Number: 1R21DE035210-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Chad Johnston | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $453,797 | Activity Code: R21 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367229