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Characterisation of the lipid II-teixobactin interaction by solid state NMR
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Fatemian, Koorosh Amir (2021) Characterisation of the lipid II-teixobactin interaction by solid state NMR. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3781085
Abstract
Antimicrobial resistance is likely to be one of the foremost challenges facing the world this century. With the number of viable antibiotics on the decline and a dearth of new antibiotics approved for use since the 1980s, new solutions are sorely needed. Recently a new antibiotic – teixobactin – was discovered that kills bacteria effectively and without the development of resistance. The target of this drug is lipid II, a bacteria cell wall precursor. Given the attractiveness of both lipid II as a target and teixobactin as a drug, understanding this interaction is a source of promise for driving drug discovery. Presented in this study is a novel method for the synthesis of 1H13C15N lipid II that was used in high resolution NMR studies with fully labelled teixobactin for the first time. These studies were combined with novel 31P NMR experiments and TEM studies to provide restraints for the calculation of a structure for the lipid II-teixobactin complex.
It was discovered that the N-terminus of teixobactin may be more involved in directly binding lipid II than previously thought. Interactions with the pentapeptide chain of lipid II are also reported here for the first time, as are dimensions of the aggregates formed by the complex. All of these findings are new insights that are not well accounted for in current models, suggesting that at the very least such models require revision. Further though, the evidence in this study suggests that the most likely conformation of the complex may not be a 1:1 antiparallel tetramer as currently suggested but in fact may favour a 2:1 parallel hexamer.
| Item Type: | Thesis (PhD) | ||||
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| Subjects: | Q Science > QC Physics Q Science > QP Physiology Q Science > QR Microbiology |
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| Library of Congress Subject Headings (LCSH): | Drug resistance in microorganisms, Nuclear magnetic resonance, Antibiotics -- Synthesis, Lipids -- Synthesis | ||||
| Official Date: | March 2021 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | School of Life Sciences | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | Lewandowski, Józef R. ; Dowson, Christopher G. | ||||
| Sponsors: | Medical Research Council (Great Britain) ; SWON Alliance | ||||
| Format of File: | |||||
| Extent: | xvi, 151 leaves : colour illustrations | ||||
| Language: | eng |
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