Doherty, Kyle (2023) Targeting Bacterial and Fungal Pathogens through Novel Glycoconjugate-based Anti-Virulence Strategies. PhD thesis, National University of Ireland Maynooth.

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Abstract

Numerous strategies have been developed to treat both bacterial and fungal infections. Of these strategies, the anti-adhesion strategy is of particular relevance to this work. Novel approaches to treat these infections are of particular importance due to the rapidly increasing prevalence of both bacterial and fungal resistant strains. Anti-virulence strategies are of interest due to an inherently lower selective pressure for resistant strains. This thesis builds on previous work in our group and presents the synthesis of novel derivatives of lead compounds developed through a combination of synthetic carbohydrate chemistry and Copper-catalysed Azide-Alkyne Cycloaddition (CuAAC). Chapter 2 describes the study of the structural requirements for an interesting intramolecular cyclisation reaction in cis-Norbornene compounds: this reaction can lead to the development of potential pH-responsive compounds. Novel anti-adhesion compounds designed to combine anti-adhesion and anti-biofilm activity based on this scaffold are discussed. Chapter 3 describes the development of glycoconjugates with covalent crosslinking abilities in combination with inherent anti-adhesion activity for C. albicans, along with toxicity testing against several Candida spp. Chapter 4 describes a structure-activity-relationship (SAR) study of our lead compound, which included replacements with heterocycles, aromatic substituents and sp2-glycomimetic analogues. Some of these derivatives exhibit comparable activity to this lead compound and open the door to the use of glycomimetics as anti-adhesion compounds in fungal infections. Additionally, a derivative of the lead compound was functionalized for resin modification and identification of the target lectin. This will ultimately allow for more efficient design of high affinity analogues. Chapter 5 describes the synthesis of a number of glycoconjugates exhibiting exciting dual anti-conjugation and anti-biofilm activities. These compounds are promising due to the key roles bacterial conjugation plays in the spread of AMR through horizontal gene transfer (HGT). Currently, preparation of fluorescently-labelled derivatives of these compounds is underway and it is hoped that this may help elucidate the mechanism of action of these compounds.

Item Type:	Thesis (PhD)
Keywords:	Targeting; Bacterial and Fungal Pathogens; Novel Glycoconjugate-based; Anti-Virulence Strategies;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	18316
Depositing User:	IR eTheses
Date Deposited:	26 Mar 2024 13:46
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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