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

<div><p>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 <em>in vitro RTA2</em> was involved in the calcineurin-mediated resistance to FLC in <em>C. albicans</em>. In this study, we found that calcium-activated-calcineurin significantly reduced the <em>in vitro</em> sensitivity of <em>C. albicans</em> to FLC by blocking the impairment of FLC to the plasma membrane <em>via</em> Rta2p. Furthermore, we found that <em>RTA2</em> itself was not involved in <em>C. albicans</em> virulence, but the disruption of <em>RTA2</em> dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one <em>RTA2</em> allele and ectopic expression of <em>RTA2</em> 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.</p>