Key physiological differences in Candida albicans CDR1 induction by steroid hormones and antifungal drugs.
The Candida albicans CDR1 gene, encoding an ABC transporter that functions as an efflux pump, is thought to be involved in pathogenic adaptation and uses mammalian hormones and other environmental cues to regulate its activity. Exposure of several clinical isolates of C. albicans to 1 x 10(-8) M 17beta-oestradiol increased CDR1 expression and the isolates showed a positive correlation between oestrogen induction of CDR1 and growth in the presence of oestrogen. A reporter strain carrying the GFP gene under the control of the CDR1 promoter was used to analyse the effect of steroid hormones and antifungal drugs on CDR1 expression by flow cytometry. We found that among the many hormones tested, only oestradiol and progesterone induce CDR1 expression. CDR1 induction requires hormone concentrations greater than 10(-8) M, a threshold reached in vivo only by progesterone. Using the GFP-reporter strain, we show CDR1 induction by female but not male human serum and demonstrate that exposure of C. albicans to physiological concentrations of progesterone measurably increases resistance to fluconazole, miconazole and 5-fluorouracil. Simultaneous exposure of C. albicans to hormones and antifungal drugs provided evidence that both agents induce CDR1 expression via different mechanisms with different saturation points.
Larsen
Bryan
B
Des Moines University, Department of Biochemistry and Nutrition, Office of University Research, The Infectious Disease Research Laboratory, 3200 Grand Avenue, Des Moines, IA 50312, USA.
Anderson
Seth
S
Brockman
Andrea
A
Essmann
Michael
M
Schmidt
Martin
M
D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D025141:Drug Resistance, Fungal; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005656:Fungal Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*
D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D049452:Green Fluorescent Proteins; D011374:Progesterone; D004958:Estradiol