Fpr1p Mediates the Synergistic Effect of Rapamycin or Tacrolimus with Caspofungin in Clavispora Lusitaniae in Vitro

Objectives Caspofungin is an echinocandin antifungal agent that inhibits glucan synthesis, an essential component of the fungal cell wall. Rapamycin and tacrolimus are immunosuppressant drugs that share the same cellular receptor, the peptidyl-prolyl isomerase Fpr1p. This study investigated the interactions between rapamycin or tacrolimus and caspofungin in inhibiting the growth of wild-type Clavispora lusitaniae and isogenic strains engineered to overexpress or lack the FPR1 gene.Methods Drug interactions were assessed using the microdilution checkerboard method in liquid medium. The results were analysed using the Fractional Inhibitory Concentration Index (FICI) and Response Surface (RS) modelling via SynergyFinder 3.0.Results Synergy was consistently observed between caspofungin and tacrolimus, as well as between caspofungin and rapamycin, in the C. lusitaniae wild-type strain across all tested combinations and analytical models. Deletion of FPR1 suppressed synergy, although a weak effect between rapamycin and caspofungin persisted in the Fpr1p-deficient strain, suggesting a small Fpr1p-independent contribution of rapamycin.Conclusions The synergistic effect of caspofungin with tacrolimus and rapamycin in C. lusitaniae is largely dependent on Fpr1p. The observed effects are likely mediated through inhibition of the calcineurin and TOR pathways, respectively.