Wednesday, April 2, 2025
4/2/2025
Bioactive natural product discovery from human oral microbes - SUMMARY Natural products, often known as specialized secondary metabolites, are used by microbes to control complex processes such as fitness, biofilm formation, nutrient acquisition, stress response, and virulence. Recent genomics and transcriptomics analysis of human oral microbiota has indicated that oral microbes have great potential to synthesize diverse natural products which are correlated with oral health or disease. However, among thousands of predicted oral natural products, less than 1% have been known. This knowledge gap prevents thorough study of natural product-mediated microbe-microbe and microbe-host interactions and hampers our understanding of the interplay between oral microbiota and host at a molecular level. There is currently an urgent need for experimental characterization of these abundant, yet poorly understood, molecules and the downstream socio-chemical relationships they mediate, which impact human oral health and disease. Our long-term goal is to harness the medical benefits that are offered by understanding chemistry and biology of oral natural products. This project focuses on the identification and characterization of bioactive natural products from the two important oral microbial species: Streptococcus mutans, a key etiological agent of human dental caries, and Streptococcus salivarius, a probiotic widely available over the counter for oral health. Following our extensive preliminary data, particularly the recent discovery and mechanistic interrogation of mutanofactin from S. mutans, we here organize our efforts into three independent specific aims to scrutinize three unique families of bioactive natural products. These oral metabolites have been predicted to play important roles in biofilm formation, acid production, or chemical defense from omics analysis and phenotypic correlations, but their chemical structures, direct biological activities and molecular mechanisms remain elusive. Using a combination of bioinformatics, microbiology, analytical chemistry, biochemistry, metabolic engineering, and molecular biology, three major questions related to these bioactive natural products will be addressed: “what is the chemical structure”, “how it is biosynthesized and regulated”, and “why it is produced”. The research strategy is both innovative and significant, because innovative multidisciplinary approaches are adopted to reveal new knowledge on oral microbial metabolism, gene functions, and molecular mechanisms of bioactive metabolites. This project is expected to reveal new targets to inform the design of prophylactics and treatments for oral disease and infection. Ultimately, new therapies may be developed to complement or synergize with traditional treatments for oral diseases such as dental caries.
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