"Sugar Coat" Genetic & chemical validation of Aspergillus fumigatus cell wall targets
type: CreativeWork
description: Aspergillus fumigatus is a filamentous fungus and considered a feared opportunistic pathogen in highly immunosuppressed patients. The spectrum and burden of clinical disease due to A. fumigatus is becoming increasingly complicated. Therapeutic management is limited to three antifungal classes (polyenes, triazoles and echinocandins) all of which have significant contraindications in terms of toxicity, drug-drug interactions and/or efficacy. With no new antifungal classes in late stage clinical trials what is required is the characterisation of new targets possessing novel modes of action. The work presented in this thesis addresses this evolving area of unmet clinical need using a target-based approach to assess a miniature portfolio of enzymes that are involved in the synthesis and remodelling of the A. fumigatus cell wall as potential antifungal targets. The cell wall of A. fumigatus is predominantly composed of chitin, β-(1,3) glucan and galactomannan and is essential for survival and structural stability. Chitin, a linear polymer of β-(1,4) linked N-acetylglucosamine (GlcNAc), forms a rigid inner layer that is also partially hydrolysed during morphogenesis by glycoside hydrolase family 18 plant-type chitinases. In contrast, exploitation of glucosamine-6-phosphate N-acetyltransferase (GNA1) an enzyme in the highly conserved UDP-GlcNAc biosynthetic pathway is an elegant means of targeting chitin synthesis upstream by inhibition of the sugar nucleotide substrate UDPGlcNAc. Finally, UDP-galactopyranose mutase (UGM) is the sole source of the galactofuranose sugar that forms short crosslinks in the outer layer of galactomannan. The underlying hypothesis is that gene deletion of A. fumigatus (i) plant-type chitinases, (ii) GNA1 and (iii) UGM produce distinctive biological phenotypes that are reproducible using small-molecule inhibitors and therefore fulfil the criteria of a “druggable” antifungal target. This work describes the discovery of novel, low micromolar chemica…
abstract: Aspergillus fumigatus is a filamentous fungus and considered a feared opportunistic pathogen in highly immunosuppressed patients. The spectrum and burden of clinical disease due to A. fumigatus is becoming increasingly complicated. Therapeutic management is limited to three antifungal classes (polyenes, triazoles and echinocandins) all of which have significant contraindications in terms of toxicity, drug-drug interactions and/or efficacy. With no new antifungal classes in late stage clinical trials what is required is the characterisation of new targets possessing novel modes of action. The work presented in this thesis addresses this evolving area of unmet clinical need using a target-based approach to assess a miniature portfolio of enzymes that are involved in the synthesis and remodelling of the A. fumigatus cell wall as potential antifungal targets. The cell wall of A. fumigatus is predominantly composed of chitin, β-(1,3) glucan and galactomannan and is essential for survival and structural stability. Chitin, a linear polymer of β-(1,4) linked N-acetylglucosamine (GlcNAc), forms a rigid inner layer that is also partially hydrolysed during morphogenesis by glycoside hydrolase family 18 plant-type chitinases. In contrast, exploitation of glucosamine-6-phosphate N-acetyltransferase (GNA1) an enzyme in the highly conserved UDP-GlcNAc biosynthetic pathway is an elegant means of targeting chitin synthesis upstream by inhibition of the sugar nucleotide substrate UDPGlcNAc. Finally, UDP-galactopyranose mutase (UGM) is the sole source of the galactofuranose sugar that forms short crosslinks in the outer layer of galactomannan. The underlying hypothesis is that gene deletion of A. fumigatus (i) plant-type chitinases, (ii) GNA1 and (iii) UGM produce distinctive biological phenotypes that are reproducible using small-molecule inhibitors and therefore fulfil the criteria of a “druggable” antifungal target. This work describes the discovery of novel, low micromolar chemica…
author: Lockhart, Deborah Ekaterina Ankerstjerne
language: eng
date published: 2014
date modified: 2026-07-24T02:08:05Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee