Molecular Mechanisms of Itraconazole Resistance in Candida dubliniensis

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dc.contributor.author Pinjon, Emmanuelle
dc.contributor.author Moran, Gary P.
dc.contributor.author Jackson, Colin J.
dc.contributor.author Kelly, Steven L.
dc.contributor.author Sanglard, Dominique
dc.contributor.author Coleman, David C.
dc.contributor.author Sullivan, Derek J.
dc.date.accessioned 2010-03-01T10:03:30Z
dc.date.available 2010-03-01T10:03:30Z
dc.date.issued 2003-08
dc.identifier.citation 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 , vol 47 , no. 8 , pp. 2424-2437 . en
dc.identifier.issn 1098-6596
dc.identifier.other PURE: 135520
dc.identifier.other dspace: 2160/4126
dc.identifier.uri http://hdl.handle.net/2160/4126
dc.description Sponsorship: Dublin Dental School and Hospital; Irish Health Research Board (grant 04-97). 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 Antimicrobial Agents and Chemotherapy en
dc.title Molecular Mechanisms of Itraconazole Resistance in Candida dubliniensis en
dc.type Text en
dc.type.publicationtype Article (Journal) en
dc.identifier.doi http://dx.doi.org/10.1128/aac.47.8.2424-2437.2003
dc.contributor.institution Institute of Biological, Environmental and Rural Sciences en
dc.description.status Peer reviewed en


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