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De novo design of antimicrobial peptides for application as anti-infective agents

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Title: De novo design of antimicrobial peptides for application as anti-infective agents
Authors: Khara, Jasmeet
Item Type: Thesis or dissertation
Abstract: 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.
Content Version: Open Access
Issue Date: Sep-2016
Date Awarded: Mar-2017
URI: http://hdl.handle.net/10044/1/45283
DOI: https://doi.org/10.25560/45283
Supervisor: Langford, Paul
Ee, Pui Lai Rachel
Sponsor/Funder: Singapore. Ministry of Health
Imperial College London Biomedical Research Centre
British Society for Antimicrobial Chemotherapy
National University of Singapore
Institute of Bioengineering and Nanotechnology, Singapore
Funder's Grant Number: NMRC/1298/2011
GA2011-01P
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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