Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature.
For several years, azole antifungal drugs have been a treatment option for potentially life-threatening Candida infections. However, azole resistance can occur through various mechanisms such as alterations in ERG11, encoding lanosterol 14alpha-demethylase (CYP51). In this study, we investigated the antifungal susceptibility to fluconazole, itraconazole, and voriconazole of 73 clinical isolates of Candida albicans. Screening for amino acid substitutions in Erg11 was performed on each of the 73 isolates. Twenty isolates displayed a marked decrease in azole susceptibility. Amino acid substitutions were detected in more than two-thirds of the strains. In all, 23 distinct substitutions were identified. Four have not been described previously, among which N136Y and Y447H are suspected to be involved in azole resistance. We suggest that the high genetic polymorphism of ERG11 must be considered in the rationale design of new azole compounds targeting lanosterol 14alpha-demethylase. A review of all Erg11 amino acid polymorphisms described to date is given.
Morio
Florent
F
Université de Nantes, Nantes Atlantique Universités, Département de Parasitologie et Mycologie Médicale, EA 1155-IICiMed, Faculté de Pharmacie, 1 Rue Gaston Veil, 44035 Nantes, France.
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Cedric
C
Besse
Bernard
B
Hennequin
Christophe
C
Le Pape
Patrice
P
D019943:Amino Acid Substitution / Q000235:genetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000235:genetics* / Q000302:isolation & purification; D002177:Candidiasis / Q000382:microbiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011743:Pyrimidines / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D058886:Sterol 14-Demethylase; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
D000935:Antifungal Agents; C548418:CYP51A1 protein, human; D004271:DNA, Fungal; D005656:Fungal Proteins; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D058886:Sterol 14-Demethylase; D065819:Voriconazole