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Title: De novo design of antimicrobial peptides for application as anti-infective agents
Author: Khara, Jasmeet
ISNI:       0000 0004 6348 3310
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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The escalating threat of antimicrobial resistance has increased pressure to develop novel therapeutic strategies to tackle drug-resistant infections. Antimicrobial peptides (AMPs) have gathered considerable interest as a new source of antibiotics due to their broad-spectrum and rapid bactericidal activities, in addition to their ability to synergise with conventional antibiotics against drug-resistant pathogens. However, natural AMPs are increasingly recognised as poor therapeutic candidates due to their long sequences, which inadvertently induce significant systemic toxicities and translate into higher manufacturing costs. To enhance their clinical utility, short synthetic analogues have been designed by fine-tuning their selectivity to preferentially interact with microbial over mammalian cells. However, the strategies employed by the majority of these studies have remained largely empirical, often utilising natural AMPs as templates, or helical wheel projections to perform modifications by replacing, deleting or scrambling amino acid sequences. Furthermore, synthetic peptides derived from natural host defence peptides possess high sequence similarity, which may promote cross-resistance when applied as therapeutic agents. Adopting a de novo approach enables the rational design of short synthetic AMPs, whilst mitigating concerns of resistance development to naturally occurring innate immune peptides. However, such rational approaches have yet to be applied to the de novo design of short synthetic anti-mycobacterial peptides. As such, this thesis first explores the feasibility of rationally designed synthetic alpha-helical AMPs as anti-tubercular agents and subsequently, a new sequence-based approach for the design of multifunctional alpha-helical peptides with idealised facial amphiphilicity, is proposed. In doing so, we demonstrate that the adoption of such systematic design principles, in the optimisation of short synthetic AMPs, could facilitate the development of safe and effective novel peptide therapeutics for application in infectious and inflammatory human diseases.
Supervisor: Langford, Paul ; Ee, Pui Lai Rachel Sponsor: Ministry of Health ; Singapore ; Imperial College London Biomedical Research Centre ; British Society for Antimicrobial Chemotherapy ; National University of Singapore ; Institute of Bioengineering and Nanotechnology ; Singapore
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral