title: The synthesis of active and stable diaminopimelate analogues of the lantibiotic peptide lactocin S.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: Avena C
authors.initials: AC
authors.lastname: Ross
authors.forename: Shaun M K
authors.initials: SM
authors.lastname: McKinnie
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001430:Bacteriocins; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007778:Lactobacillus / Q000187:drug effects* / Q000254:growth & development; D008089:Listeria monocytogenes / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010376:Pediococcus / Q000187:drug effects* / Q000254:growth & development; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D010455:Peptides; C103925:lactocin S; D003960:Diaminopimelic Acid