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Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC) increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that  in vitro RTA2  was involved in the calcineurin-mediated resistance to FLC in  C. albicans . In this study, we found that calcium-activated-calcineurin significantly reduced the  in vitro  sensitivity of  C. albicans  to FLC by blocking the impairment of FLC to the plasma membrane  via  Rta2p. Furthermore, we found that  RTA2  itself was not involved in  C. albicans  virulence, but the disruption of  RTA2  dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one  RTA2  allele and ectopic expression of  RTA2  significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium-activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies.

Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p