Clostridium difficile infection (CDI) is responsible for 250,000 infections and 14,000 deaths annually. High rates of treatment failure, recurrent infections, and potential for antibiotic resistance are all evidence that new and effective treatments for are needed. A potential treatment for CDI is auranofin, which forms a stable adduct with selenium, thereby disrupting the selenium-dependent anaerobic pathways in C. difficile. Auranofin was previously used to treat rheumatoid arthritis (RA), but was discontinued as it was poorly absorbed and had adverse effects such as mild diarrhoea. The pharmacokinetics of auranofin are ideally suited to GI infections such as CDI. The aim of this study is to assess the potential of auranofin as an adjunctive therapy to treat CDI.
Conservation of the selenium dependent proteins, such as glycine reductase protein A, proline reductase protein A and B and selenophosphate synthase were confirmed using Sanger sequencing.
The effect of auranofin on C. difficile growth was tested on CD01 (ribotype UKI-001) which is the most commonly isolated ribotype in Australia. Growth assays using optical density and viable cell counts were used to show that auranofin inhibits the growth of C. difficile at concentration of 6µM when compared to the control (p=0.0023). Further assays will test the effect auranofin has on sporulation and toxin. Auranofin will also be compared to metronidazole, the current treatment for non-severe CDI, as well as metronidazole and auranofin combined to test auranofin as an adjunctive therapy.
The high level of conservation of selenoproteins combined with evidence that modulating selenium metabolism inhibits C. difficile growth indicates that selenium targeted therapy has the potential to improve the clinical outcomes of CDI. Auranofin is capable of inhibiting C. difficile growth in culture at concentrations much lower than the dose which resulted in adverse effects during RA treatment. This supports the notion that Auranofin could improve the outcome of CDI therapy when given in combination with metronidazole, potentially reducing the rate of recurrent cases.