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dc.contributor.author Sullivan, Derek J.
dc.contributor.author Kelly, Steven L.
dc.contributor.author Moran, Gary P.
dc.contributor.author Coleman, David C.
dc.contributor.author Jackson, Colin J.
dc.contributor.author Pinjon, Emmanuelle
dc.contributor.author Sanglard, Dominique
dc.date.accessioned 2009-12-21T10:10:43Z
dc.date.available 2009-12-21T10:10:43Z
dc.date.issued 2009-12-21
dc.identifier.citation Sullivan , D J , Kelly , S L , Moran , G P , Coleman , D C , Jackson , C J , Pinjon , E & Sanglard , D 2009 , ' Molecular mechanisms of itraconazole resistance in Candida dubliniensis ' Unknown Journal , pp. 2424-2437 . en
dc.identifier.other PURE: 145980
dc.identifier.other dspace: 2160/3871
dc.identifier.uri http://hdl.handle.net/2160/3871
dc.description Pinjon, E., Moran, G. P., Jackson, C. J., Kelly, S. L., Sanglard, D., Coleman, D. C., Sullivan, D. J. (2003). Molecular mechanisms of itraconazole resistance in Candida dubliniensis.   Antimicrobial Agents and Chemotherapy, 47, (8), 2424-2437 en
dc.description.abstract It has previously been shown that overexpression of the CdMDR1 gene is a major contributor to resistance in fluconazole-resistant isolates of Candida dubliniensis. However, since CdMdr1p does not mediate transport of other azole drugs such as itraconazole, we investigated the molecular mechanisms of stable resistance to itraconazole obtained in three strains of C. dubliniensis (two with nonfunctional CdCDR1 genes and one with functional CdCDR1 genes) by serial exposure to this antifungal agent in vitro. Seven derivatives that were able to grow on agar medium containing 64 µg of itraconazole per ml were selected for detailed analysis. These derivatives were resistant to itraconazole, fluconazole, and ketoconazole but were not cross resistant to inhibitors. CdMDR1 expression was unchanged in the seven resistant derivatives and their parental isolates; however, all seven derivatives exhibited increased levels of CdERG11 expression, and six of the seven derivatives exhibited increased levels of CdCDR1 expression compared to the levels of expression by their respective parental isolates. Except for one derivative, the level of rhodamine 6G efflux was decreased in the itraconazole-resistant derivatives compared to the level of efflux in their parental isolates, suggesting altered membrane properties in these derivatives. Analysis of their membrane sterol contents was consistent with a defective sterol C5,6-desaturase enzyme (CdErg3p), which was confirmed by the identification of mutations in the alleles (CdERG3) encoding this enzyme and their lack of functional complementation in a Saccharomyces cerevisiae erg3 mutant. The results of this study show that the loss of function of CdErg3p was the primary mechanism of in vitro-generated itraconazole resistance in six of the seven the C. dubliniensis derivatives. However, the mechanism(s) of itraconazole resistance in the remaining seventh derivative has yet to be determined. en
dc.format.extent 14 en
dc.language.iso eng
dc.relation.ispartof Unknown Journal en
dc.title Molecular mechanisms of itraconazole resistance in Candida dubliniensis en
dc.type Text en
dc.type.publicationtype Article (Journal) en
dc.contributor.institution Institute of Biological, Environmental and Rural Sciences en
dc.description.status Peer reviewed en


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