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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM058822-18
Application #
9274983
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
1999-02-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
18
Fiscal Year
2017
Total Cost
$246,769
Indirect Cost
$37,969
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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
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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