Murtza, Aamina;
(2023)
Molecular Design and Biophysical Studies of a New Class of Lipid IIbinding Antibiotics.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The rise of antibiotic resistance has instigated research into new therapies that employ different mechanisms to traditional antibiotics. Lantibiotics are a promising class of post-translationally modified peptides that have the potential to overcome resistance, but their clinical applications are limited by their low in vivo stability. One such class I lantibiotic, nisin, has been extensively studied at a molecular and mechanistic level. Despite its use as a preservative for the last 50 years, significant resistance has not been reported. The lantibiotic nisin functions via a dual mode of action, nisin N-terminus inhibits cell wall synthesis by sequestering lipid II, whilst the C-terminus inserts itself into the membrane forming a (8:4) nisin: lipid II pore complex. To enable nisin to be used clinically, researchers must determine the minimum structural requirements that allow for the lipid II binding and pore-forming activities of nisin for optimisation. Previous solution-state NMR studies have established the role of nisin AB rings in binding to lipid II. Here in, we have designed partially linearised analogues, in which the lipid II binding moiety (AB or ABC rings) are bioconjugated onto linear analogues of the C-terminus of nisin. The synthesis of nisin AB-linearCDE and progress towards other analogues, is described. This project has also focused on synthesising partially linearised nisin click analogues where the native amide bond has been substituted for the triazole amide bond mimic, to establish if click chemistry is a viable cross-stapling technique for the rapid production of nisin analogues. The nisin recognition, pore-forming, and antimicrobial properties of these constructs have been measured by collaboration in chemistry and biochemical engineering and the results are discussed. Understanding the roles of cyclisation in the C ring and the D/E rings in lipid II binding and pore-formation will enable us to design more potent semisynthetic antimicrobial peptides.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Molecular Design and Biophysical Studies of a New Class of Lipid IIbinding Antibiotics |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10175011 |
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