Abstract: The Human Microbiome Project (HMP) is generating a wealth of data about the composition and dynamics of human-associated microbial communities, and other recent efforts have shown that changes in the composition of the microbiome are correlated with human diseases. This proposal, which originated with my laboratory's recent and unexpected finding that human-associated bacteria produce drug-like small molecules, will use HMP data as a starting point for identifying and characterizing new small molecules from human-associated microbes. There are three convergent motivations for this project: First, the HMP, an NIH Roadmap Initiative, is generating a wealth of data about the composition and dynamics of human-associated microbial communities. New connections between the composition of the microbiome and human disease are being discovered with increasing frequency, but functional studies are needed to translate this data into new therapies. This project will build one such bridge, using HMP data to support functional studies on human-associated bacteria that could lead to new probiotic therapies. Second, small molecules from human-associated bacteria are likely to have important activities. Given the strong precedent for microbially-produced small molecules to mediate interspecies interactions, small molecules from the human microbiome are likely to mediate intra-microbiome and host- microbiome interactions, both of which will have an important bearing on human health. This project will use HMP data to identify and characterize new small molecules from the human microbiome that mediate interspecies interactions. Third, engineered probiotics are likely to be common in the future, and will be one of the most direct benefits to human health from the Human Microbiome Project. Unlike the human genome, the human microbiome is a component of our 'supra-genome'whose composition we can control. This project will lay the groundwork for engineering new probiotic bacterial strains, creating the potential for a direct link from the HMP to the clinic. Public Health Relevance: Natural products - small molecules from microbes - have been a primary source of clinically-used antibiotics, antifungals, anticancer agents, immunosuppressants, and other drugs. This proposal describes new approaches to discovering and characterizing natural products from an unusual source: human-associated microbes. Identifying and characterizing these molecules will not only lead to a greater understanding of the connection between the human microbiome and human disease, it will also lay the groundwork for engineering new probiotic bacterial strains (like the bacteria found in yogurt) that could promote human health and help fight diseases like Crohn's disease and obesity.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s New Innovator Awards (DP2)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-NDIA-O (01))
Program Officer
Basavappa, Ravi
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Pharmacy
San Francisco
United States
Zip Code
Wilks, Jessica; Lien, Egil; Jacobson, Amy N et al. (2015) Mammalian Lipopolysaccharide Receptors Incorporated into the Retroviral Envelope Augment Virus Transmission. Cell Host Microbe 18:456-62
Wang, Qi; Rosa, Bruce A; Nare, Bakela et al. (2015) Targeting Lysine Deacetylases (KDACs) in Parasites. PLoS Negl Trop Dis 9:e0004026
Taketani, Mao; Donia, Mohamed S; Jacobson, Amy N et al. (2015) A Phase-Variable Surface Layer from the Gut Symbiont Bacteroides thetaiotaomicron. MBio 6:e01339-15
Schulze, Christopher J; Donia, Mohamed S; Siqueira-Neto, Jair L et al. (2015) Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei. ACS Chem Biol 10:2373-81
Medema, Marnix H; Fischbach, Michael A (2015) Computational approaches to natural product discovery. Nat Chem Biol 11:639-48
Claesen, Jan; Fischbach, Michael A (2015) Synthetic microbes as drug delivery systems. ACS Synth Biol 4:358-64
Devlin, A Sloan; Fischbach, Michael A (2015) A biosynthetic pathway for a prominent class of microbiota-derived bile acids. Nat Chem Biol 11:685-90
Donia, Mohamed S; Fischbach, Michael A (2015) HUMAN MICROBIOTA. Small molecules from the human microbiota. Science 349:1254766
Donia, Mohamed S; Cimermancic, Peter; Schulze, Christopher J et al. (2014) A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell 158:1402-1414
Lau, Warren; Fischbach, Michael A; Osbourn, Anne et al. (2014) Key applications of plant metabolic engineering. PLoS Biol 12:e1001879

Showing the most recent 10 out of 26 publications