title: Reduced azole susceptibility in genotype 3 Candida dubliniensis isolates associated with increased CdCDR1 and CdCDR2 expression.
abstract: Candida dubliniensis is a recently identified yeast species primarily associated with oral carriage and infection in individuals infected with the human immunodeficiency virus. The species can be divided into at least four genotypes on the basis of the nucleotide sequence of the internal transcribed spacer region of the rRNA operon. Previous studies have shown that a small number of clinical isolates belonging to genotype 1 are resistant to the commonly used antifungal drug fluconazole. The aim of the present study was to investigate the molecular mechanisms responsible for reduced susceptibility to azole drugs in C. dubliniensis genotype 3 isolates obtained from a patient with fluconazole-recalcitrant oral candidiasis. Four isolates from a single clinical sample, one susceptible, the other three exhibiting reduced susceptibilities to fluconazole, itraconazole, ketoconazole, voriconazole, and posaconazole, were examined. Results showed that reduced susceptibility to azole drugs was associated with an increase in the expression of the multidrug transporters CdCDR1 and CdCDR2 which correlated with reduced intracellular accumulation of radiolabeled fluconazole and an increase in the activity of energy-dependent efflux mechanisms. In contrast to observations made in previous studies, overexpression of the multidrug transporter CdMDR1 was not observed. Despite a thorough investigation of all commonly encountered mechanisms of azole resistance, no other mechanism could be associated with reduced susceptibility to azole drugs in the clinical isolates studied. This is the first report of CdCDR2 involvement in azole resistance in C. dubliniensis.
authors.affiliation: Microbiology Research Unit, Department of Oral Medicine and Oral Pathology, School of Dental Science and Dublin Dental Hospital, Trinity College, University of Dublin, Dublin 2, Republic of Ireland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Pinjon
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Jackson
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kelly
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.forename: Gary
authors.initials: G
authors.lastname: Moran
authors.forename: David C
authors.initials: DC
authors.lastname: Coleman
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Sullivan
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001393:Azoles / Q000494:pharmacology* / Q000627:therapeutic use; D002175:Candida / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002180:Candidiasis, Oral / Q000188:drug therapy / Q000382:microbiology; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology / Q000627:therapeutic use; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015854:Up-Regulation
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D001393:Azoles; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D015725:Fluconazole