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Title: Studies related to the mode of action of glycopeptide antibiotics
Author: Gale, T. F.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2001
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Research into glycopeptide antibiotics is of great importance because these therapies offer a last resort in the treatment of lethal, hospital-acquired infections. Particularly desirable are understandings of both the co-operativity involved in the mode of action of vancomycin-group antibiotics and the pathways by which they are biosynthesised. Chapter 2 presents evidence for the context-dependency of carboxylic acid dimerisation and discusses the implications of the binding of glycopeptide antibiotics to the cell walls of infectious bacteria. The findings extend previously published ideas concerning the phenomenon of enthalpic co-operativity in non-covalent complexes. Chapters 3 and 4 report synthetic modifications to vancomycin designed to increase the extent of co-operativity in the cell wall binding of the antibiotic, and hence its bacteriocidal potency. The first approach to this end involved N-terminal modifications to vancomycin and binding studies of the novel derivatives to a tripeptide mimic of the antibiotic's wild-type target. Although only weaker binding is observed the results shed light on some suitable factors which contribute to the strong binding of the parent antibiotic. A second approach, discussed in Chapter 4, involved the tethering of vancomycin and penicillin, a synthetic challenge approached using solid-phase peptide synthesis. The final part of this manuscript focuses on some aspects of glycopeptide antibiotic biosynthesis. Chapter 5 discusses the non-ribosomal assembly of the glycopeptide backbone and describes the synthesis of isotopically-labelled N-methylleucine intended for use in biological feeding studies. Chapter 6 discusses the biosynthesis of a rare deoxysugar which occurs in certain members of the vancomycin group. The cloning and expression of a transaminase involved in its biosynthetic pathway is described.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available