Biol. Pharm. Bull. 30(1) 68—73 (2007)

fungal pathogen in humans, causes diseases varying from superficial mucosal complaints to life-threatening systemic disorders. Coincident with the increased use of antifungal drugs, the incidences of drug resistance have also increased. In recent years, the development of multidrug resistance in clinical isolates has challenged effective treatment of the infections. Specifically, the extensive and repetitive use of antifungal azole derivatives such as fluconazole (FLC) has allowed C. albicans to utilize many mechanisms of resistance in order to ensure its survival. This situation highlights the need for elucidating the mechanism of drug resistance in C. albicans to develop new antifungal agents. Overexpression of efflux pumps, either ATP-binding cassette (ABC) or major facilitator superfamily (MFS) transporters, has been shown to be one of the major mechanisms of drug resistance in clinical isolates because if causes active extrusion of the drug out of the cell. The Candida drug resistance 1 (CDR1) gene, which encodes an ABC efflux pump, is identified by complementation of the pleiotropic drug resistance 5 (pdr5) mutant, which is hypersensitive to cycloheximide, chloramphenicol, and azole drugs, in Saccharomyces cerevisiae (S. cerevisiae). C. albicans cdr1 mutant resulted in increasing susceptibilities to azole drugs, which is consistent with the observation that overexpression of CDR1 contributes to the drug resistance of clinical isolates of C. albicans. Furthermore, the existence of trans-regulatory factors of CDR1 has also been suggested. However, the molecular mechanism and the gene network regulating the expression of CDR1 and drug resistance are poorly understood. C. albicans Fcr1p (for fluconazole resistance 1 protein), a member of the family of zinc cluster proteins, is characterized by a highly conserved Zn(II)2Cys6 zinc finger motif within the N-terminal DNA binding domain (DBD). Well known Pdr1p and Pdr3p (pleiotropic drug resistance protein) zinc cluster proteins regulate the expression of several multidrug ABC transporter genes including PDR5, SNQ2, and YOR1, causing azole resistance in S. cerevisiae. C. albicans Fcr1p displays significant sequence homology with S. cerevisiae Pdr1p and Pdr3p, and it could confer azole resistance in S. cerevisiae pdr1 pdr3 mutant by regulating PDR5. We hypothesized that Fcr1p maybe involved in the development of C. albicans azole resistance as well as Pdr1p and Pdr3p in S. cerevisiae. In the present study we investigated the role of Fcr1p in the development of C. albicans azole resistance and possible mechanisms in vitro and in vivo. The results showed that Fcr1p inhibited development of fluconazole resistance in C. albicans through abolishing the induction of CDR1 expression by FLC, and in contrast FLC resistance development was accelerated resulting from the deletion of FCR1.