Author ORCID Identifier

https://orcid.org/0000-0001-5888-2382

Document Type

Theses, Ph.D

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1.6 BIOLOGICAL SCIENCES

Publication Details

A thesis submitted to Technological University Dublin – City Campus for the degree of Doctor of Philosophy, May 2022.

Abstract

Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is an urgent need to develop novel therapeutic agents to overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. Interdisciplinary research in inorganic medicinal chemistry with biology is advancing the knowledge and implementation of transition metal complexes for therapy and is offering a realistic alternative to traditional antibiotics. Metal complexes with 1,10-phenanthroline (phen) ligands have demonstrated promising therapeutic capabilities with diverse biological activity. Consequently, there has been a resurgence in research of these complexes as possible alternatives or adjuvants to established antimicrobial clinical therapeutics. The antibacterial and anti-biofilm activity of novel metal complexes (metal = Cu(II), Mn(II), and Ag(I)) incorporating phen and various dicarboxylate ligands was the focus of this research.

The Cu(II), Mn(II), and Ag(I) chelates incorporating both phen and the dianion of 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the activity varied depending on the metal centre. All three metal-tdda-phen complexes showed comparable and often superior activity to the established antibiotic gentamicin clinical P. aeruginosa isolates from cystic fibrosis (CF) lungs of Irish patients, concerning biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and were supported by the reduction of the individual biofilm components examined. The efficacy of individual treatments of Cu-tdda-phen, Mn-tdda-phen, and Ag-tdda-phen and in combination with gentamicin were further examined in vivo, utilising the larvae of Galleria mellonella infected with CF isolates. All test complexes were tolerated by G. mellonella in concentrations up to 10 µg/larva and affected the host's immune response by stimulating immune cells (hemocytes) and enhancing the expression of genes that encode for immune-related peptides. Combining the metal-tdda-phen complexes with gentamicin further intensified this response at lower concentrations, clearing a P. aeruginosa infection previously resistant to gentamicin alone. Therefore, this work highlights the anti-pseudomonal capabilities of metal-tdda-phen complexes alone and combined with gentamicin in a valuable pre-clinical in vivo model.

DOI

https://doi.org/10.21427/82em-dy71

Funder

The Fiosraigh Dean of Graduate Students Scholarship

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