RRC ID 46842
著者 Costa C, Pires C, Cabrito TR, Renaudin A, Ohno M, Chibana H, Sá-Correia I, Teixeira MC.
タイトル Candida glabrata drug:H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1.
ジャーナル Antimicrob Agents Chemother
Abstract The widespread emergence of antifungal drug resistance poses a severe clinical problem. Though predicted to play a role in this phenomenon, the drug:H(+) antiporters (DHA) of the major facilitator superfamily have largely escaped characterization in pathogenic yeasts. This work describes the first DHA from the pathogenic yeast Candida glabrata reported to be involved in antifungal drug resistance, the C. glabrata QDR2 (CgQDR2) gene (ORF CAGL0G08624g). The expression of CgQDR2 in C. glabrata was found to confer resistance to the antifungal drugs miconazole, tioconazole, clotrimazole, and ketoconazole. By use of a green fluorescent protein (GFP) fusion, the CgQdr2 protein was found to be targeted to the plasma membrane in C. glabrata. In agreement with these observations, CgQDR2 expression was found to decrease the intracellular accumulation of radiolabeled clotrimazole in C. glabrata and to play a role in the extrusion of this antifungal from preloaded cells. Interestingly, the functional heterologous expression of CgQDR2 in the model yeast Saccharomyces cerevisiae further confirmed the role of this gene as a multidrug resistance determinant: its expression was able to complement the susceptibility phenotype exhibited by its S. cerevisiae homologue, QDR2, in the presence of imidazoles and of the antimalarial and antiarrhythmic drug quinidine. In contrast to the findings reported for Qdr2, CgQdr2 expression does not contribute to the ability of yeast to grow under K(+)-limiting conditions. Interestingly, CgQDR2 transcript levels were seen to be upregulated in C. glabrata cells challenged with clotrimazole or quinidine. This upregulation was found to depend directly on the transcription factor CgPdr1, the major regulator of multidrug resistance in this pathogenic yeast, which has also been found to be a determinant of quinidine and clotrimazole resistance in C. glabrata.
巻・号 57(7)
ページ 3159-67
公開日 2013-7-1
DOI 10.1128/AAC.00811-12
PII AAC.00811-12
PMID 23629708
PMC PMC3697362
MeSH ATP-Binding Cassette Transporters / metabolism Antifungal Agents / pharmacology* Antiporters / metabolism* Candida glabrata / drug effects* Candida glabrata / metabolism Clotrimazole / pharmacology Drug Resistance, Fungal / genetics* Gene Expression Regulation, Fungal Green Fluorescent Proteins Imidazoles / pharmacology* Ketoconazole / pharmacology Miconazole / pharmacology Microbial Sensitivity Tests Saccharomyces cerevisiae / metabolism Transcription Factors / genetics Transcription Factors / metabolism
IF 4.904
引用数 40
WOS 分野 PHARMACOLOGY & PHARMACY MICROBIOLOGY
リソース情報
病原微生物