Fungi as Eukaryotes: Understanding the Antifungal Effects of Immunosuppressive Drugs

The immunosuppressive agents cyclosporine, tacrolimus, and sirolimus are naturally occurring products of environmental fungi or bacteria, so the fact that they possess intrinsic antifungal activity is not surprising. Both calcineurin and the target of rapamycin (TOR) are conserved across eukaryotes and share a common function, regulating the organism’s ability to react to environmental changes and response to stress. In the medically important fungi Candida, Cryptococcus, and Aspergillus, mutations in the calcineurin gene affect in vitro patterns of growth and serum sensitivity, and attenuate virulence in animal models. Notably, cyclosporine, tacrolimus, and sirolimus exhibit strong synergy with many classes of antifungal drugs including azoles, amphotericin B, and the echinocandins, with potentiation of fungicidal effects even against drug-resistant strains. Hopefully, future studies will realize the promise of exploiting the antifungal properties of the immunosuppressive drugs to help decrease the burden of these clinically important infections on patient survival.