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.
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.
|van der Donk, Wilfred A; Nair, Satish K (2014) Structure and mechanism of lanthipeptide biosynthetic enzymes. Curr Opin Struct Biol 29:58-66|
|Ortega, Manuel A; Velásquez, Juan E; Garg, Neha et al. (2014) Substrate specificity of the lanthipeptide peptidase ElxP and the oxidoreductase ElxO. ACS Chem Biol 9:1718-25|
|Garcia De Gonzalo, Chantal V; Zhu, Lingyang; Oman, Trent J et al. (2014) NMR structure of the S-linked glycopeptide sublancin 168. ACS Chem Biol 9:796-801|
|Wang, Huan; Oman, Trent J; Zhang, Ran et al. (2014) The glycosyltransferase involved in thurandacin biosynthesis catalyzes both O- and S-glycosylation. J Am Chem Soc 136:84-7|
|Garg, Neha; Oman, Trent J; Andrew Wang, Tsung-Shing et al. (2014) Mode of action and structure-activity relationship studies of geobacillin I. J Antibiot (Tokyo) 67:133-6|
|Zhang, Qi; Ortega, Manuel; Shi, Yanxiang et al. (2014) Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS. Proc Natl Acad Sci U S A 111:12031-6|
|Mukherjee, Subha; van der Donk, Wilfred A (2014) Mechanistic studies on the substrate-tolerant lanthipeptide synthetase ProcM. J Am Chem Soc 136:10450-9|
|Bindman, Noah A; van der Donk, Wilfred A (2013) A general method for fluorescent labeling of the N-termini of lanthipeptides and its application to visualize their cellular localization. J Am Chem Soc 135:10362-71|
|Tang, Weixin; van der Donk, Wilfred A (2013) The sequence of the enterococcal cytolysin imparts unusual lanthionine stereochemistry. Nat Chem Biol 9:157-9|
|Garg, Neha; Salazar-Ocampo, Luis M A; van der Donk, Wilfred A (2013) In vitro activity of the nisin dehydratase NisB. Proc Natl Acad Sci U S A 110:7258-63|
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