Lanthipeptides are post-translationally modified peptide with a variety of biological activities. Nisin, its best known member, has been used for decades in the food industry without significant development of resistance. Other lanthipeptides are under investigation or in clinical trials for the treatment of cystic fibrosis and for the treament of multi-drug resistant bacteria. In this grant application we seek to extend our past success towards the use of the biosynthetic machinery as tools for biotechnology and to better understand their mechanism of substrate recognition and catalysis. Our goals are: 1. Understand the enzymes involved in lanthipeptide biosynthesis. 2. Engineer efficient processes to use posttranslationally modified peptide natural products for various applications. 3. Investigate new posttranslationally modified peptide natural products.
The appearance of multi-drug resistant bacterial strains is well documented. The bacterial genome sequencing efforts have shown that all known natural products (the main source of our current antibiotics) cover only a very small fraction of the genetic capacity of microorganisms to produce these compounds. This available genomic information has made genome mining a potentially productive route to new natural product antibiotics, which is what this program is focused on.
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| Hegemann, Julian D; van der Donk, Wilfred A (2018) Investigation of Substrate Recognition and Biosynthesis in Class IV Lanthipeptide Systems. J Am Chem Soc 140:5743-5754 |
| Repka, Lindsay M; Hetrick, Kenton J; Chee, See Hyun et al. (2018) Characterization of Leader Peptide Binding During Catalysis by the Nisin Dehydratase NisB. J Am Chem Soc 140:4200-4203 |
| Bobeica, Silvia C; van der Donk, Wilfred A (2018) The Enzymology of Prochlorosin Biosynthesis. Methods Enzymol 604:165-203 |
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| Ortega, Manuel A; Cogan, Dillon P; Mukherjee, Subha et al. (2017) Two Flavoenzymes Catalyze the Post-Translational Generation of 5-Chlorotryptophan and 2-Aminovinyl-Cysteine during NAI-107 Biosynthesis. ACS Chem Biol 12:548-557 |
| Cubillos-Ruiz, Andres; Berta-Thompson, Jessie W; Becker, Jamie W et al. (2017) Evolutionary radiation of lanthipeptides in marine cyanobacteria. Proc Natl Acad Sci U S A 114:E5424-E5433 |
| Burkhart, Brandon J; Kakkar, Nidhi; Hudson, Graham A et al. (2017) Chimeric Leader Peptides for the Generation of Non-Natural Hybrid RiPP Products. ACS Cent Sci 3:629-638 |
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