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Title: Synthesis and conformational studies of the lipid II-binding rings of nisin and mutacin I
Author: Dickman, Rachael
ISNI:       0000 0004 7232 6851
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Antibiotic resistance is a huge global health threat, and there is urgent need for new classes of antimicrobials to combat the spread of resistant organisms. In recent years, a class of antimicrobial peptides called the lantibiotics has emerged as a promising potential source of new antibiotics. The first discovered lantibiotic, nisin, has become a model compound for the class. It displays extremely potent antibacterial activity, but its poor pharmacokinetic properties mean that it is currently unable to be used therapeutically. This thesis describes the synthesis and structural analysis of the target-binding region of nisin and its close structural relative mutacin I. The lantibiotics are characterised by their complex cyclic structures formed by the unusual bis-amino acids lanthionine and methyllanthionine, and frequently contain the dehydrated amino acids dehydroalanine and dehydrobutyrine. To synthesise these peptides, methods to introduce each of these unusual residues are required. Therefore, the first aim of this research was to synthesise two orthogonally protected (methyl)lanthionines, as well as various precursors to the dehydrated residues. With these in hand, several novel truncated analogues of nisin and mutacin I were synthesised. Simpler analogues with fewer unusual amino acids were prepared, as well as peptides with the wild-type sequence. Finally, the solution state structure of each of the peptides was calculated from NMR data. From these studies, key conformational differences were observed between the synthesised truncated analogues in comparison to both full length and truncated wild-type nisin. In addition, significant differences were seen between the wild-type peptides and the simplified analogues. Taken together, these results indicate which of the unusual amino acids it may be possible to substitute whilst still maintaining native solution structure. It is hoped that this will guide future analogue design, and aid in the development of new semisynthetic antibiotics based on the structure of nisin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available