title: A clinical isolate of Candida albicans with mutations in ERG11 (encoding sterol 14alpha-demethylase) and ERG5 (encoding C22 desaturase) is cross resistant to azoles and amphotericin B.
abstract: A clinical isolate of Candida albicans was identified as an erg5 (encoding sterol C22 desaturase) mutant in which ergosterol was not detectable and ergosta 5,7-dienol comprised >80% of the total sterol fraction. The mutant isolate (CA108) was resistant to fluconazole, voriconazole, itraconazole, ketoconazole, and clotrimazole (MIC values, 64, 8, 2, 1, and 2 microg ml(-1), respectively); azole resistance could not be fully explained by the activity of multidrug resistance pumps. When susceptibility tests were performed in the presence of a multidrug efflux inhibitor (tacrolimus; FK506), CA108 remained resistant to azole concentrations higher than suggested clinical breakpoints for C. albicans (efflux-inhibited MIC values, 16 and 4 microg ml(-1) for fluconazole and voriconazole, respectively). Gene sequencing revealed that CA108 was an erg11 erg5 double mutant harboring a single amino acid substitution (A114S) in sterol 14alpha-demethylase (Erg11p) and sequence repetition (10 duplicated amino acids), which nullified C22 desaturase (Erg5p) function. Owing to a lack of ergosterol, CA108 was also resistant to amphotericin B (MIC, 2 microg ml(-1)). This constitutes the first report of a C. albicans erg5 mutant isolated from the clinic.
authors.affiliation: Institute of Life Science and School of Medicine, Swansea University, Swansea SA2 8PP, Wales, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Martel
authors.forename: Josie E
authors.initials: JE
authors.lastname: Parker
authors.forename: Oliver
authors.initials: O
authors.lastname: Bader
authors.forename: Michael
authors.initials: M
authors.lastname: Weig
authors.forename: Uwe
authors.initials: U
authors.lastname: Gross
authors.forename: Andrew G S
authors.initials: AG
authors.lastname: Warrilow
authors.forename: Diane E
authors.initials: DE
authors.lastname: Kelly
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics*; D025141:Drug Resistance, Fungal / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D016133:Polymerase Chain Reaction
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D000666:Amphotericin B