Berberine inhibits fluphenazine-induced up-regulation of CDR1 in Candida albicans.
Over-expression of the Candida drug resistance gene CDR1 is a common mechanism generating azole-resistant Candida albicans in clinical isolates. CDR1 is transcriptionally activated through the binding of the transcription factor Tac1p to the cis-acting drug-responsive element (DRE) in its promoter. We previously demonstrated that the combination of fluconazole (FLC) and berberine (BBR) produced significant synergy when used against FLC-resistant C. albicans in vitro. In this study, we found that BBR inhibited both the up-regulation of CDR1 mRNA and the transport function of Cdr1p induced by fluphenazine (FNZ). Further, electrophoretic mobility shift assays suggested that the transcription activation complex of protein-DRE was disrupted by BBR, and electrospray ionization mass spectrometry analysis showed that BBR bound to the DRE of CDR1. Thus we propose that BBR inhibits the FNZ-induced transcriptional activation of CDR1 in C. albicans by blocking transcription factor binding to the DRE of CDR1. These results contribute to our understanding of the mechanism of synergistic effect of BBR and FLC.
Center for New Drug Research, School of Pharmacy, Second Military Medical University.
Shao-Long
SL
Zhu
Lan
L
Yan
Yan-Xia
YX
Zhang
Zhi-Hui
ZH
Jiang
Ping-Hui
PH
Gao
Yue
Y
Qiu
Liang
L
Wang
Ming-Zhu
MZ
Zhao
Ting-Jun-Hong
TJ
Ni
Zhan
Z
Cai
Shu-Juan
SJ
Tian
Cheng-Xu
CX
Zang
Da-Zhi
DZ
Zhang
Yuan-Ying
YY
Jiang
D000935:Antifungal Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004357:Drug Synergism; D005476:Fluphenazine / Q000009:adverse effects* / Q000627:therapeutic use; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation
D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D010936:Plant Extracts; D012333:RNA, Messenger; D001599:Berberine; D005476:Fluphenazine