title: Calcium-activated-calcineurin reduces the In vitro and In vivo sensitivity of fluconazole to Candida albicans via Rta2p.
abstract: 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.
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jia
authors.forename: Ren-Jie
authors.initials: RJ
authors.lastname: Tang
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Jia
authors.forename: Yuan-Ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology*; D002176:Candida albicans / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D058387:Candidemia / Q000188:drug therapy; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015725:Fluconazole / Q000494:pharmacology* / Q000627:therapeutic use; D005656:Fungal Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D051379:Mice
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D015725:Fluconazole; D019703:Calcineurin; D002118:Calcium