The Synthesis of Active and Stable Diaminopimelate Analogues of the Lantibiotic Peptide Lactocin S

Lantibiotic peptides are potent antimicrobial compounds produced by Gram-positive bacteria. They can be used in food preservation, and some also show potential for clinical applications. Unfortunately, some of these peptides can be susceptible to inactivation by oxidation of the sulfur-containing am...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2012-02, Vol.134 (4), p.2008-2011
Main Authors: Ross, Avena C, McKinnie, Shaun M. K, Vederas, John C
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Diaminopimelic Acid - analogs & derivatives
Diaminopimelic Acid - chemistry
Diaminopimelic Acid - pharmacology
Dose-Response Relationship, Drug
Lactobacillus - drug effects
Lactobacillus - growth & development
Listeria monocytogenes - drug effects
Listeria monocytogenes - growth & development
Microbial Sensitivity Tests
Molecular Conformation
Pediococcus - drug effects
Pediococcus - growth & development
Peptides - chemical synthesis
Peptides - chemistry
Peptides - pharmacology
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Summary:Lantibiotic peptides are potent antimicrobial compounds produced by Gram-positive bacteria. They can be used in food preservation, and some also show potential for clinical applications. Unfortunately, some of these peptides can be susceptible to inactivation by oxidation of the sulfur-containing amino acid lanthionine, limiting their use. Here we describe the synthesis and testing of diaminopimelate analogues of the lantibiotic lactocin S. These analogues were designed to improve the oxidative stability of the peptide by replacing the sulfur in lanthionine with a methylene unit. Lanthionine was systematically replaced with diaminopimelate during solid-phase peptide synthesis to produce several analogues. One analogue, A-DAP lactocin S, was found to retain full biological activity in addition to displaying increased stability. This is the first time a synthetic lanthionine ring analogue of a lantibiotic has retained natural activity levels. This methodology is potentially very promising for use in producing more stable, medically relevant lantibiotics.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja211088m