It has recently become appreciated that ribosomal peptide natural products (RiPPs) represent one of the major groups of bioactive natural products on Earth. The compounds are found nearly universally in bacteria, where they place diverse roles including quorum signaling, cofactor synthesis, and chemical defense. Most commonly, RiPPs exhibit potent antibiotic activity. They are key players in modern drug discovery and development. Perhaps more importantly, RiPPs present an enormous storehouse of posttranslational machinery that can be used to design drug-like compounds. They are readily manipulated for the rational engineering and optimization of desired properties. In this proposal, we will use this diverse RiPP biosynthetic machinery to better understand posttranslational enzymes, to optimize and engineer production platforms, and to develop technologies to better harness these complex pathways in the design and discovery of new antibiotics.
Our specific aims are to: 1) Characterize unique RiPP posttranslational enzymes using chemical, biochemical, and genetic methods;2) Improve compound production and analog synthesis in heterologous hosts;3) Discover new antibiotics by implementing novel bioassays.
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| Morita, Maho; Hao, Yue; Jokela, Jouni K et al. (2018) Post-Translational Tyrosine Geranylation in Cyanobactin Biosynthesis. J Am Chem Soc 140:6044-6048 |
| Sardar, Debosmita; Hao, Yue; Lin, Zhenjian et al. (2017) Enzymatic N- and C-Protection in Cyanobactin RiPP Natural Products. J Am Chem Soc 139:2884-2887 |
| Hao, Yue; Pierce, Elizabeth; Roe, Daniel et al. (2016) Molecular basis for the broad substrate selectivity of a peptide prenyltransferase. Proc Natl Acad Sci U S A 113:14037-14042 |
| Sardar, Debosmita; Schmidt, Eric W (2016) Combinatorial biosynthesis of RiPPs: docking with marine life. Curr Opin Chem Biol 31:15-21 |
| Sardar, D; Tianero, M D; Schmidt, E W (2016) Directing Biosynthesis: Practical Supply of Natural and Unnatural Cyanobactins. Methods Enzymol 575:1-20 |
| Tianero, Ma Diarey; Pierce, Elizabeth; Raghuraman, Shrinivasan et al. (2016) Metabolic model for diversity-generating biosynthesis. Proc Natl Acad Sci U S A 113:1772-7 |
| Lin, Zhenjian; Torres, Joshua P; Tianero, M Diarey et al. (2016) Origin of Chemical Diversity in Prochloron-Tunicate Symbiosis. Appl Environ Microbiol 82:3450-60 |
| Sardar, Debosmita; Lin, Zhenjian; Schmidt, Eric W (2015) Modularity of RiPP Enzymes Enables Designed Synthesis of Decorated Peptides. Chem Biol 22:907-16 |
| Sardar, Debosmita; Pierce, Elizabeth; McIntosh, John A et al. (2015) Recognition sequences and substrate evolution in cyanobactin biosynthesis. ACS Synth Biol 4:167-76 |
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