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A Calcineurin Inhibitor as an Enhancer of Candida Susceptibility to Anidulafungin
Irene Rovira1, Edurne Montemayor2, Sandra Gil-Alonso3
1Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena, s/n, 48940 Bilbao, Spain.
Abstract:
The increase in invasive candidiasis caused by emerging Candida species presents a significant medical challenge due to their resistance to conventional antifungal treatments. Exploring novel therapeutic strategies, such as drug repurposing, is therefore essential. Tacrolimus, an immunosuppressive calcineurin inhibitor, shows potential antifungal effects. This study investigated the in vitro effect of combining tacrolimus and echinocandin anidulafungin using the checkerboard method against 60 clinical Candida isolates, including Candida albicans, Candida auris, Candida glabrata, and Candida parapsilosis. Time-kill assays against C. parapsilosis clinical isolates with FKS1 gene mutations were conducted. Checkerboard data revealed that tacrolimus reduced anidulafungin MIC values: a synergistic activity was observed against 90% of the isolates studied, with a particularly notable effect against multidrug-resistant C. auris, showing 100% synergy. Positive outcomes were corroborated by time-kill assays. Hence, the addition of tacrolimus may enhance susceptibility to anidulafungin, as suggested by checkerboard and time-kill assays conducted against C. parapsilosis, including isolates harboring mutations in FKS1. These promising findings are a starting point for future studies on the antifungal properties of tacrolimus and related compounds.
Insights
Tacrolimus combined with anidulafungin shows synergistic antifungal activity against challenging Candida species. This drug repurposing approach enhances susceptibility, offering a promising strategy against invasive candidiasis.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Pharmacology
Background:
- Emerging Candida species cause invasive candidiasis, posing treatment challenges due to antifungal resistance.
- Drug repurposing of existing medications like tacrolimus is a key strategy for novel antifungal therapies.
Purpose of the Study:
- To investigate the in vitro synergistic antifungal effects of combining tacrolimus with anidulafungin.
- To evaluate this combination against various clinical Candida isolates, including drug-resistant strains.
Main Methods:
- Checkerboard microdilution assays were used to determine drug interactions (MIC values).
- Time-kill assays were performed on specific Candida parapsilosis isolates with FKS1 mutations.
- Sixty clinical Candida isolates were tested, including Candida albicans, Candida auris, Candida glabrata, and Candida parapsilosis.
Main Results:
- Tacrolimus demonstrated synergistic activity with anidulafungin against 90% of tested Candida isolates.
- 100% synergy was observed against multidrug-resistant Candida auris.
- Time-kill assays corroborated the synergistic findings, indicating enhanced anidulafungin susceptibility.
Conclusions:
- Combining tacrolimus with anidulafungin shows significant synergistic antifungal potential.
- This combination may overcome resistance mechanisms in Candida species, including those with FKS1 mutations.
- Tacrolimus and related compounds warrant further investigation as antifungal agents.
