Studies on the Synthesis of Unusual Amino Acids and their incorporation into new Peptide Antibiotics
Document Type
Theses, Ph.D
Rights
Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence
Disciplines
1.4 CHEMICAL SCIENCES
Abstract
As microorganisms continue to develop resistance and survive against many different forms of antimicrobial solutions, such as antibiotics, there is urgent need for new classes of antimicrobial peptides to mitigate the threat. Bacteria are a rich source of ribosomally-synthesized antimicrobial peptides known as bacteriocins, which are produced by one bacterial species to kill other bacterial strains. Lanthionine-containing lantibiotics and sactibiotics are post-translationally modified bacteriocins which display extremely potent antibacterial activity.
Thuricin CD, a two-peptide system belonging to the sactibiotic family, shows high activity, but most importantly excellent selectivity, against C. difficile infection. The Thuricin CD peptides contain a number of highly unusual quaternary α-amino acid residues with a sulfur to α-carbon link (SAC). To synthesise these peptides, methods to introduce unusual SAC building blocks into peptide structure are required. Therefore, the first aim of this research was to synthesise quaternary α-amino acid residues with a sulfur to α-carbon link.
A well-studied lantibiotic, nisin, which has a polycyclic peptide structure of 34 amino acids, is currently used worldwide as a food preservative in dairy, meat and tinned-food products. It is an antimicrobial agent against Gram-positive bacteria, but is unstable at physiological pH, in part due to the reactive dehydroalanine residue at position 5 in the A ring. Development of nisin analogues with increased stability, while also maintaining high bioactivity, would greatly enhance the possible use of a nisin analogue as a theraputic agent. The next project aim was to synthesise an analogue of the A-ring of nisin by replacing Dha5 by a cyclopropyl residue (AC3C).
An interesting feature of many lantibiotics is the similarity among their A-ring fragments. They contain the same number of amino acid residues, with the Dha and lanthionine (thioether link) residues present in all of the structures. The major difference between the various A-rings are the amino acids residues flanking the Dha moiety. Finally, this thesis investigates how amino acids beside Dha could affect the peptide conformation as well as its physicochemical properties.
DOI
https://doi.org/10.21427/envb-dz79
Recommended Citation
Wadolowska, A. (2020). Studies on the Synthesis of Unusual Amino Acids and their incorporation into new Peptide Antibiotics. Technological University Dublin. DOI: 10.21427/ENVB-DZ79
Publication Details
A Thesis Presented For the Award of Doctor of Philosophy, Technological University Dublin, 2020.