Piatek, Magdalena (2023) Evaluation of the mode of action of novel metal-based antimicrobial compounds. PhD thesis, National University of Ireland Maynooth.

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Abstract

The global threat of antimicrobial resistance (AMR) is steadily on the rise jeopardising the efficacy of conventional antimicrobial agents. This crisis is driven by the inappropriate use of antimicrobials and decline in novel drug discovery. The most threatening pathogens have developed resistance to multiple drug classes and demand particular attention. Part of the ESKAPE pathogen list, Staphylococcus aureus and Pseudomonas aeruginosa are major causes of severe nosocomial infection and frequent colonisers of cystic fibrosis patient lungs. Moreover, Candida and Aspergillus spp. contribute to the vast majority of fungal infections and exacerbate morbidity and mortality in the immunocompromised. Metal ions have a long history of antimicrobial use however, the advent of AMR and the desire for more innovative strategies have revived interest. Metal ions possess unique (and multiple) modes of action. In addition, the diverse physiochemical properties of metal-based complexes (e.g. coordination number, geometry, reactivity and type and number of ligands) enables the production of vast libraries of agents with differing properties. Indeed, the design, synthesis, characterisation and microbiological assessment relies upon an interdisciplinary approach in the fields of inorganic chemistry and biology. This project conducted microbiological assessment of novel gallium(III)- and silver(I)-based agents whereby drug candidates were screened against a range of bacterial and fungal pathogens. The most susceptible of which were subjected to label-free quantitative proteomic analysis to uncover the likely mechanistic roles. The iron-mimicking capabilities of gallium and resulting disruption in iron ion homeostasis has led to the generation of therapeutic formulations including gallium maltolate (GaM). Anti-Pseudomonal assessment in vitro translated in vivo using Galleria mellonella as an insect model whilst subsequent proteomic studies revealed a number of affected pathways which would contribute to the attenuated growth and virulence of the pathogen. The poor bioavailability of gallium compounds prompted the development of water-soluble heteroleptic Ga(III) polypyridyl compounds ([Ga(bipy)2(2,3-DHBA-2H)](NO3) (1), [Ga(bipy)2(3,4-DHBA-2H)](NO3) (2) and [Ga(bipy)2(2,3,4-THBA-2H)](NO3) (3)) bearing a catecholate moiety. These siderophore conjugates, which aimed to enhance gallium uptake, were evaluated against Aspergillus fumigatus. Proteomic and biochemical analyses revealed the superior activity of these novel agents to existing gallium nitrate and effect on mitochondria. Subsequent work analysed the antimicrobial activity of the silver(I) N-heterocyclic carbene (NHC) complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*), termed SBC3. Alterations in the Candida parapsilosis proteome revealed a significant decrease in protein synthesis and directed further studies on the anti-virulence capacities of SBC3 in terms of cell adhesion, biofilm formation and cell morphology. Possessing broad-spectrum activity, SBC3 was also examined against two structurally different bacteria: P. aeruginosa (Gram-negative) and S. aureus (Gram-positive). Both were susceptible to SBC3 treatment however, proteomic findings identified distinct variations in affected proteins and associated pathways. The results presented in this thesis offer novel insights on the activity of these selected metal complexes for the treatment of resistant microbial pathogens. Proteomic analysis is a useful tool in drug discovery and development, which is key in addressing escalating rates of AMR.

Item Type:	Thesis (PhD)
Keywords:	Evaluation; mode of action; novel metal-based antimicrobial compounds;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	18303
Depositing User:	IR eTheses
Date Deposited:	21 Mar 2024 15:55
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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