Lantibiotics are post-translationally modified peptide antibiotics. Nisin, its best known member, has been used for decades in the food industry without significant development of resistance. Other lantibiotics are under investigation or in clinical trials for the treatment of cystic fibrosis and asthma, the elimination of tooth-decay causing bacteria, and for the treatment of multi-drug resistant bacteria. In this grant application we seek to extend our past success towards the use of the biosynthetic machinery to make analogs and to better understand their mechanism of substrate recognition and catalysis. Our goals are: 1. Understand the enzymes involved in crosslink formation 2. Engineer efficient processes to manipulate the structures of posttranslationally modified peptide natural products 3. Investigate new posttranslationally modified peptide natural products.

Public Health Relevance

Numerous reports of multi-drug resistant bacterial strains have appeared in recent years, with several strains posing the serious threat of becoming immune against all commercially available antibiotics. It is evident that in order to prevent potential epidemic outbreaks of infectious diseases, a renewed focus on antibiotic research is highly desired. The group of posttranslationally modified peptide antibiotics has much promise as a new line of defense against pathogenic bacteria and many members are under evaluation for human applications. Currently, no methods exist for in depth medicinal chemistry on these compounds to improve their pharmacological properties. This research program seeks to improve technology that will allow doing this by relying on the biosynthetic machinery. Furthermore, we propose studies to better understand the enzymes involved in crosslink formation in this grant application. Additionally, we will extend our work to new promising compounds and will investigate the use of the lantibiotic enzymes for applications other than lantibiotic engineering.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058822-14
Application #
8519466
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Gerratana, Barbara
Project Start
1999-02-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$266,504
Indirect Cost
$42,624
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
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Zhao, Xiling; van der Donk, Wilfred A (2016) Structural Characterization and Bioactivity Analysis of the Two-Component Lantibiotic Flv System from a Ruminant Bacterium. Cell Chem Biol 23:246-56
Walker, Mark C; van der Donk, Wilfred A (2016) The many roles of glutamate in metabolism. J Ind Microbiol Biotechnol 43:419-30
Thibodeaux, Christopher J; Wagoner, Joshua; Yu, Yi et al. (2016) Leader Peptide Establishes Dehydration Order, Promotes Efficiency, and Ensures Fidelity During Lacticin 481 Biosynthesis. J Am Chem Soc 138:6436-44
Zhang, Zhengan; Hudson, Graham A; Mahanta, Nilkamal et al. (2016) Biosynthetic Timing and Substrate Specificity for the Thiopeptide Thiomuracin. J Am Chem Soc 138:15511-15514
Ortega, Manuel A; van der Donk, Wilfred A (2016) New Insights into the Biosynthetic Logic of Ribosomally Synthesized and Post-translationally Modified Peptide Natural Products. Cell Chem Biol 23:31-44
Ding, Wei; Liu, Wan-Qiu; Jia, Youli et al. (2016) Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes. Proc Natl Acad Sci U S A 113:3521-6
Huo, Liujie; van der Donk, Wilfred A (2016) Discovery and Characterization of Bicereucin, an Unusual d-Amino Acid-Containing Mixed Two-Component Lantibiotic. J Am Chem Soc 138:5254-7
Garg, Neha; Goto, Yuki; Chen, Ting et al. (2016) Characterization of the stereochemical configuration of lanthionines formed by the lanthipeptide synthetase GeoM. Biopolymers 106:834-842
Ortega, Manuel A; Hao, Yue; Walker, Mark C et al. (2016) Structure and tRNA Specificity of MibB, a Lantibiotic Dehydratase from Actinobacteria Involved in NAI-107 Biosynthesis. Cell Chem Biol 23:370-80

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