Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597628
Title: Studies related to the vancomycin group of antibiotics
Author: Cho, Y. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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Abstract:
Dimerisation is important in the mode of action of the clinically-important vancomycin group of glycopeptide antibiotics. NMR studies have shown that one member of this group, ristocetin A, forms an asymmetric dimer with two physically different binding sites for cell-wall peptide analogues. Ligand binding and dimerisation are slightly anti-cooperative. In contrast, for the other glycopeptide antibiotics that have been examined so far, binding of cell-wall peptides and dimerisation are cooperative. Chapter two presents NMR evidence that the two halves of the asymmetric homodimer formed by ristocetin A have different affinities for ligand binding. One site is preferentially filled before the other, and binding to this site is cooperative with dimerisation. Ligand binding to the other, less favoured site, is anti-cooperative with dimerisation. Chapter three describes the synthesis of cell-wall depsipeptide analogues present in vancomycin-resistant strains of bacteria. The depsipeptide has been covalently modified by adding acyl chains on the C-terminus. The depsipeptides can anchor via their acyl chain to a phosphatidylcholine vesicle, and together they provide a model membrane surface of vancomycin-resistant bacteria. Chapter four describes cooperative interactions between the antibiotic, chloroeremomycin, and anchored depsipeptides to the model vesicle surface described above. The binding affinity of chloroeremomycin was found to be more than 10,000-fold greater to anchored depsipeptides as compared to depsipeptides in solution, illustrating the importance of templated interactions. Chapter five describes preliminary work aimed at generating an alternative therapeutic agent, monoclonal antibodies, against both vancomycin-susceptible and -resistant strains of bacteria.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.597628  DOI: Not available
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