Calcineurin is essential for survival during membrane stress in Candida albicans.
The immunosuppressants cyclosporin A (CsA) and FK506 inhibit the protein phosphatase calcineurin and block T-cell activation and transplant rejection. Calcineurin is conserved in microorganisms and plays a general role in stress survival. CsA and FK506 are toxic to several fungi, but the common human fungal pathogen Candida albicans is resistant. However, combination of either CsA or FK506 with the antifungal drug fluconazole that perturbs synthesis of the membrane lipid ergosterol results in potent, synergistic fungicidal activity. Here we show that the C.albicans FK506 binding protein FKBP12 homolog is required for FK506 synergistic action with fluconazole. A mutation in the calcineurin B regulatory subunit that confers dominant FK506 resistance (CNB1-1/CNB1) abolished FK506-fluconazole synergism. Candida albicans mutants lacking calcineurin B (cnb1/cnb1) were found to be viable and markedly hypersensitive to fluconazole or membrane perturbation with SDS. FK506 was synergistic with fluconazole against azole-resistant C.albicans mutants, against other Candida species, or when combined with different azoles. We propose that calcineurin is part of a membrane stress survival pathway that could be targeted for therapy.
Cruz
M Cristina
MC
Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Goldstein
Alan L
AL
Blankenship
Jill R
JR
Del Poeta
Maurizio
M
Davis
Dana
D
Cardenas
Maria E
ME
Perfect
John R
JR
McCusker
John H
JH
Heitman
Joseph
J
D000935:Antifungal Agents / Q000494:pharmacology; D001483:Base Sequence; D015152:Blotting, Northern; D019703:Calcineurin / Q000502:physiology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D017931:DNA Primers; D004352:Drug Resistance, Microbial; D015725:Fluconazole / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D005800:Genes, Fungal; D008780:Methyltransferases / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology
D000935:Antifungal Agents; D017931:DNA Primers; D016572:Cyclosporine; D015725:Fluconazole; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase; D019703:Calcineurin; D016559:Tacrolimus