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Title: Complementary peptide switching: implications in innate immune regulatory mechanisms
Author: Ryan, Lloyd Eugene
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2013
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The rise of antibiotic resistance demands the development of new antimicrobial agents. These should exhibit a novel mechanism of action so as to overcome the resistance and be invulnerable to 'not yet acquired resistance mechanisms'. Such criteria are difficult to meet, however cationic host defence peptides (HOPs) have emerged as promising candidates. HOPs target and disrupt bacterial membranes via simple physio-chemical interactions and the fundamental nature of this target raises the possibility of antimicrobial drugs based on HOP being invulnerable to the development of widespread resistance. Despite this apparent invulnerability, localised resistance to HOP does exist and the use of HOP as drugs will create new selective pressure which bacteria may be able to respond to. Herein a new potential resistance mechanism to helical HOPs in both de novo and native systems is presented. In this work coiled-coil folding was tested as a HOP regulatory system: • Anionic anti-sequences were designed to form coiled - coil dimers with peptides from three classes of naturally occurring HOP. • Native HOP sequences were mutated to identify regions of the sequences able to resist coiled-coil formation. • Successful systems were subject to biological testing to asses viability of the complexes as a microbial HOP resistance mechanism The results provide a new insight into potential resistance mechanisms to HOP and they should serve to place constraints on the design of synthetic HOP sequences. The results may be used as inspiration in the search for novel antimicrobial drug targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available