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.