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Synthesis and biological evaluation of the lantibiotic peptide lactocin S and its analogues Open Access


Other title
lactocin S
peptide synthesis
Type of item
Degree grantor
University of Alberta
Author or creator
Ross, Avena Clara
Supervisor and department
Vederas, John C. (Chemistry)
Examining committee member and department
McMullen, Lynn M. (Agricultural, Food and Nutritional Science)
Clive, Derrick L. J. (Chemistry)
Bergens, Steven H. (Chemistry)
Dawson, Philip E. (External)
Cairo, Christopher W. (Chemistry)
Vederas, John C. (Chemistry)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Lantibiotics (lanthionine containing antibiotics) are highly post-translationally modified peptides used by bacteria as a form of chemical warfare. In light of the challenges faced today in the field of antibacterial therapy, these potent natural products are useful lead compounds for the development of future antibiotics. Lactocin S (98) is a 37 amino acid lantibiotic peptide isolated from Lactobacillus sakei L45. Due to low levels of production by the natural producer organism, complete structural identification has been challenging. The total chemical synthesis of 98 using a combined solution and solid phase chemistry approach is described. The unusual amino acid lanthionine was synthesized in solution with orthogonal protecting groups (58) so that it could be cyclized on-resin during the solid phase synthesis of the peptide. An N-terminal α-ketoamide precursor was also made in solution. Following coupling to the rest of the peptide on resin, global deprotection of the peptide resulted in the formation of the α-ketoamide containing lactocin S (98). A simplified purification of lactocin S (98) from Lactobacillus sakei L45 was developed. Comparison of the natural and synthetic peptides via activity testing, mass spectrometry and chiral GC/MS analysis confirmed the proposed structure of lactocin S (98). Unfortunately, lactocin S suffers from pH and oxidative instability. This thesis describes the synthesis of analogues developed with a goal of improving stability as well as activity. The lanthionine rings were systematically replaced with diaminopimelate, which contains a methylene carbon in place of the thioether of lanthionine. Orthogonally protected diaminopimelate (137) was synthesized via a key photolysis reaction of diacylperoxide 170 to form the backbone. The solid phase synthesis of the analogues was then accomplished. One of these analogues, A-DAP lactocin S (151), exhibited improved activity compared to the natural peptide (98). A second site of modification was methionine 12. Leucine (181) and norleucine (182) analogues were made that exhibit full retention of activity. A final analogue (183) was synthesized using an oxazole ring to mimic the dehydrobutyrine-α-ketoamide functionality at the N-terminus of lactocin S (98). This compound displayed no biological activity. The methodology described, provides access to potentially stable and active analogues of lantibiotics.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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