GENE DISRUPTION OF THE CANDIDA ALBICANS ECM22 GENE, RELATED TO THE SACCHAROMYCES CEREVISIAE TRANSCRIPTION FACTOR ECM22 AND THE STEROL UPTAKE GENE UPC2, INCREASES SUSCEPTIBILITY TO A WIDE RANGE OF ANTIFUNGAL DRUGS

Silver PM, White TC

Author address: 

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Abstract: 

In Candida albicans, drug resistance to clinically important antifungal drugs may be regulated through the action of transcription factors in a manner similar to S. cerevisiae. The near completion of the C. albicans sequencing project has allowed the identification of a C. albicans homolog of the S. cerevisiae genes ECM22 and UPC2. Deletion of the S. cerevisiae ECM22 gene has been previously associated with increased susceptibility to calcofluor white, a chitin binding and cell wall perturbing agent. The S. cerevisiae UPC2 gene has been linked to regulation of sterol uptake across the plasma membrane. The ECM22 gene in C. albicans was deleted through homologous recombination using the URA3 and ARG4 selectable markers. Parental, single deletion, double deletion, and revertant strains of ECM22 were tested against a battery of antifungal drugs including the azole class drugs fluconazole, itraconazole, and ketoconazole. The ECM22 double deletion strains showed a marked hypersusceptibility to all azoles tested when compared to parental, with increases in susceptibility of 23 to 65 fold. Single disruption strains exhibited an intermediate response. Hypersusceptibility in the ECM22 deletion mutants was also observed for ergosterol biosynthesis inhibitors terbinafine and fenpropimorph, with increases in susceptibility of 50 and 125 fold respectively, and for the chitin inhibiting drugs nikkomycinZ and calcofluor white with increases in susceptibility of 32 and 16 fold respectively. Sequence analysis of the ECM22 gene suggests a bipartite protein containing a regulatory/binding domain located in the ER membrane and a cleavable transcription factor containing multiple nuclear localization signals and a fungal zinc(2)-cys(6) binuclear cluster domain. These observations suggest that ECM22 is a transcription factor involved in the maintenance of antifungal drug susceptibility in C. albicans.
2003

abstract No: 

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Full conference title: 

The 15 th Congress of the International Society for Human and Animal Mycology
    • ISHAM 15th (2003)