Serum repressing efflux pump CDR1 in Candida albicans.
BACKGROUND
In 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.


RESULTS
The 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.


CONCLUSIONS
Our 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.
Yang
Yun-Liang
YL
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu. yyang@mail.nctu.edu.tw
Lin
Yi-Hsuan
YH
Tsao
Ming-Yang
MY
Chen
Chia-Geun
CG
Shih
Hsin-I
HI
Fan
Jen-Chung
JC
Wang
Jang-Shiun
JS
Lo
Hsiu-Jung
HJ
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D003470:Culture Media; D004268:DNA-Binding Proteins / Q000235:genetics; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D049410:Luciferases, Renilla; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D044967:Serum; D014157:Transcription Factors / Q000235:genetics
D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D003470:Culture Media; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; C495215:Ndt80 protein, Candida albicans; D014157:Transcription Factors; D015725:Fluconazole; D049410:Luciferases, Renilla