Antimicrobial resistance (AMR) represents a current global burden which affects patients worldwide, with a projected 1.27 million deaths by 2025. Due to the rise of AMR, clinically used antibacterial treatments are becoming less effective and resistance to first-line drugs is increasing. Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram-positive pathogen which exhibits multidrug-resistance to a range of antimicrobial compounds. As it employs multiple complex resistance mechanisms, MRSA complicates the treatment of infections and poses a significant threat to healthcare systems and public health. Supramolecular chemistry provides an alternative approach to antimicrobial therapy by exploiting self-assembly to readily modulate compounds and tailor their properties to achieve specific desirable biological responses. Ligands L1 and L2, capable of forming complexes with metal ions (Zn2+, Mn2+ and Cu2+) via self-assembly, were shown to encapsulate metal ions and bind them through non-covalent interactions, electrostatic interactions and hydrogen bonding. The resulting metal-ligand complexes exhibited antimicrobial activity against several Gram-positive bacterial pathogens (MRSA, vancomycin-resistant Enterococcus faecium, Bacillus subtilis). Each metal-ligand complex showed different antimicrobial profiles, demonstrating that modulating the metal ion or modifying the ligand structure can tune the biological activity of the complexes. Structure-activity relationships enabled the identification of the most effective complex against specific bacterial strains. Notably, no antimicrobial activity was observed against Gram-negative bacterial pathogen, Escherichia coli. Interestingly, MRSA samples treated with the experimental compounds showed enhancement of bactericidal activity when incubated under illuminated conditions, with bactericidal activity at concentrations similar to those of vancomycin. Additionally, the L1 complexes were shown to exhibit intrinsic fluorescence, due to the presence of a coumarin-containing unit inside the ligand. These species can bind to and stain bacterial cells, enabling their visualisation under UV light illumination, through fluorescence emission. Confocal microscopy analysis confirmed that the compound was able to enter bacterial cell and associate to the outer membrane. Furthermore, a skin penetration assay using a porcine skin model demonstrated limited penetration of the compound through the skin, supporting its potential for topical treatment applications for bacterial infections.
| Date of Award | 27 Aug 2026 |
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| Original language | English |
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| Supervisor | Craig Rice (Main Supervisor) |
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