Abstract
BackgroundIn the past decades, the prevalence of candidemia has increased significantly and drug resistance has also become a pressing problem. Overexpression of CDR1, an efflux pump, has been proposed as a major mechanism contributing to the drug resistance in Candida albicans. It has been demonstrated that biological fluids such as human serum can have profound effects on antifungal pharmacodynamics. The aim of this study is to understand the effects of serum in drug susceptibility via monitoring the activity of CDR1 promoter of C. albicans.ResultsThe wild-type C. albicans cells (SC5314) but not the cdr1/cdr1 mutant cells became more susceptible to the antifungal drug when the medium contained serum. To understand the regulation of CDR1 in the presence of serum, we have constructed CDR1 promoter-Renilla luciferase (CDR1p-RLUC) reporter to monitor the activity of the CDR1 promoter in C. albicans. As expected, the expression of CDR1p-RLUC was induced by miconazole. Surprisingly, it was repressed by serum. Consistently, the level of CDR1 mRNA was also reduced in the presence of serum but not N-acetyl-D-glucosamine, a known inducer for germ tube formation.ConclusionOur finding that the expression of CDR1 is repressed by serum raises the question as to how does CDR1 contribute to the drug resistance in C. albicans causing candidemia. This also suggests that it is important to re-assess the prediction of in vivo therapeutic outcome of candidemia based on the results of standard in vitro antifungal susceptibility testing, conducted in the absence of serum.
Highlights
In the past decades, the prevalence of candidemia has increased significantly and drug resistance has become a pressing problem
We have found that the wild-type SC5314 cells but not the cdr1/cdr1 mutant cells became more susceptible to fluconazole, a commonly used antifungal drug, when the medium contained serum
To determine if serum has any effect on the drug susceptibility of C. albicans, we have determined the growth of cells in the presence of different concentrations of fluconazole and in the absence or presence of 10% fetal bovine serum
Summary
The prevalence of candidemia has increased significantly and drug resistance has become a pressing problem. Overexpression of CDR1, an efflux pump, has been proposed as a major mechanism contributing to the drug resistance in Candida albicans. Overexpression of CDR1, an ATP binding cassette (ABC) transporter, has been shown to be the major mechanism for the drug resistance of clinical isolates [3]. The expression of CDR1 is increased approximately 4-fold in Catup1/Catup mutant cells, which are predominately in the hyphal form [6]. This data suggests that CaTup acts as a negative regulator of CDR1. Two transcription factors, CaNDT80 and CaTAC1, have been identified as positive regulators of CDR1 in C. albicans [7,8]
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