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Durham e-Theses
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Antimicrobial Peptoids: Design, Synthesis and Biological Applications

BOLT, HANNAH,LOUISE (2016) Antimicrobial Peptoids: Design, Synthesis and Biological Applications. Doctoral thesis, Durham University.

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The emergence of antimicrobial resistance is a severe threat to global health and new classes of antibiotics are desperately needed. Peptoids, or oligo-N-substituted glycines, are a group of peptidomimetics with increased structural stability and resistance to protease degradation compared to peptide analogues. In Chapter 1, peptoids are introduced and their antimicrobial properties reported to date are summarised. The synthesis and characterisation of one of the largest library of antimicrobial peptoids in existence is outlined in Chapter 2, comprising linear sequences and cyclic compounds. The development of synthetic methodology that allows the on-resin synthesis of novel peptoids containing both lysine- and arginine-type monomers is also described. In Chapter 3, the antiparasitic activity of the peptoid library is assessed against a variety of clinically relevant protozoan targets; including Leishmania mexicana, the causative agent of the neglected tropical disease cutaneous leishmaniasis. Active peptoids were identified against the insect and mammalian life stages of this parasite, including several with low micromolar potency against L. mexicana infected macrophages, an in vivo model of the disease. Additionally, peptoids that have selective activity at sub-micromolar concentrations against Plasmodium falciparum have been identified. Chapter 4 discusses the potent antibacterial and antifungal properties of the peptoid library against planktonic bacteria and also against mixed species, cross kingdom biofilms using a new quantitative polymerase chain reaction approach. Evaluation of peptoid toxicity to mammalian cells is also considered and conjugation of active sequences to the lantibiotic nisin is evaluated as a method to increase peptoid selectivity. To rationalise the activity of the peptoid library, Chapter 5 investigates the relationship between peptoid hydrophobicity, secondary structure and biological activity using circular dichroism spectroscopy and partitioning experiments. Finally, the antimicrobial mode of action is also examined using confocal fluorescence microscopy.

Item Type:Thesis (Doctoral)
Award:Doctor of Philosophy
Keywords:peptoids, peptidomimetics, synthesis, antiparasitic, antibacterial, leishmaniasis
Faculty and Department:Faculty of Science > Chemistry, Department of
Thesis Date:2016
Copyright:Copyright of this thesis is held by the author
Deposited On:16 Jan 2017 14:40

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