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.
| Yang, Xiao; Lennard, Katherine R; He, Chang et al. (2018) A lanthipeptide library used to identify a protein-protein interaction inhibitor. Nat Chem Biol 14:375-380 |
| 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 |
| Hetrick, Kenton J; Walker, Mark C; van der Donk, Wilfred A (2018) Development and Application of Yeast and Phage Display of Diverse Lanthipeptides. ACS Cent Sci 4:458-467 |
| Kakkar, Nidhi; Perez, Jessica G; Liu, Wenshe R et al. (2018) Incorporation of Nonproteinogenic Amino Acids in Class I and II Lantibiotics. ACS Chem Biol 13:951-957 |
| Si, Tong; Tian, Qiqi; Min, Yuhao et al. (2018) Rapid Screening of Lanthipeptide Analogs via In-Colony Removal of Leader Peptides in Escherichia coli. J Am Chem Soc 140:11884-11888 |
| Huo, Liujie; Ökesli, Ay?e; Zhao, Ming et al. (2017) Insights into the Biosynthesis of Duramycin. Appl Environ Microbiol 83: |
| Repka, Lindsay M; Chekan, Jonathan R; Nair, Satish K et al. (2017) Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes. Chem Rev 117:5457-5520 |
| Funk, Michael A; van der Donk, Wilfred A (2017) Ribosomal Natural Products, Tailored To Fit. Acc Chem Res 50:1577-1586 |
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