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Title: Cooperativity in the mode of action of the vancomycin group antibotics
Author: Bardsley, B.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1998
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Abstract:
The vancomycin group of antibiotics are currently the last line of defence, in hospitals, against methicillin-resistant Staphylococcus aureus (MRSA). Increasingly, bacterial species are being isolated in hospitals which are resistant also to vancomycin and teicoplanin (the two members of the group in clinical use). There is thus great importance in establishing an understanding of their mode of action and, in particular, features of their mode of action which may be utilised in the design of new antibotics, which are active against vancomycin-resistant bacteria. This dissertation seeks to explore aspects of cooperativity in these antibiotics' mode of action and also to consider their implications in biological systems. The primary tool for these investigations has been 1H NMR spectroscopy. The antibiotic ristocetin A is the only member of the vancomycin group where ligand binding is anticooperative with dimerisation. It is shown that selective modification of the antibiotic structure results in the reversal of this anticooperativity and the reasons for this reversal are discussed. The asymmetric nature of the homodimers formed by these antibiotics and the effect of this asymmetry on ligand binding is explored by measurement of the affinities of ligand for each half of the dimer. The results are considered in the light of previous observations regarding the anticooperative ristocetin A system. The aglycone member of the vancomycin group, LY154989, is characterised by 1H NMR and its ligand binding and dimerisation properties investigated. These results are considered with respect to the structural features that affect the magnitude of these properties. Finally, other aspects of cooperativity in the vancomycin group antibiotics' mode of action is investigated. The enhancement to binding when the constituents are located at a surface is investigated and the relationship between dimerisation constant and hydrogen bond lengths at the dimer interface is investigated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.596353  DOI: Not available
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