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Combining fusidic acid with metal ions as a potential reformulation for the treatment of bacterial keratitis

Boostrom, Hannah 2019. Combining fusidic acid with metal ions as a potential reformulation for the treatment of bacterial keratitis. PhD Thesis, Cardiff University.
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Fusidic acid is a protein synthesis inhibitor commonly used to treat Gram-positive infections caused by pathogens such as Staphylococcus aureus. Gram-negative bacteria are intrinsically resistant due to their low permeability outer membrane and efflux pumps. UK optometrists are licenced to prescribe fusidic acid for the treatment of bacterial eye infections. However, 45 % cases of bacterial keratitis – a severe, sight-threatening corneal infection – are caused by Gram-negative organisms. As some metal ions have been found to enhance the activity and extend the spectrum of established antimicrobial drugs, this work sought to investigate the efficacy of combining metal ions with fusidic acid as a potential reformulation strategy to repurpose fusidic acid as a broad spectrum, first line treatment for bacterial keratitis. The presence of Al3+, Cu2+ or Fe2+ ions was found to increase the activity of the fusidic acid sodium salt, sodium fusidate, against a selection of multi-drug resistant Gram-negative Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa isolates, without reducing anti-S. aureus efficacy. P. aeruginosa was particularly susceptible to sodium fusidate with Al3+. There was no apparent link between the carriage of multi-drug resistance determinants and susceptibility to the combinations. With no evidence of spontaneous complexation, the mechanism of action against E. coli was determined to be reduced fusidate solubility enabling increased membrane access combined with the independent antimicrobial activity of metal ions. Proliferation of human corneal epithelial cells was less inhibited by Al3+, Cu2+ or Fe2+ than the Gram-negative reference strains, suggesting clinical selectivity. Unfortunately, the combinations were inactive against Gram-negatives in a novel rationalised simulated tear fluid, likely due to protein binding of both agents. However, future formulation optimisation may overcome this issue. Finally, the discovery of Al3+ and sodium fusidate activity against P. aeruginosa has prompted further research into the combined mechanism of action in this important opportunistic pathogen.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 23 April 2020
Last Modified: 23 Apr 2020 08:51

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