GENETIC POLYMORPHISM OF THE ERG11 GENE IN CLINICAL ISOLATES OF CANDIDA ALBICANS: FUNDAMENTAL AND APPLIED ASPECTS
Azoles are the most representative group of antifungal agents for the treatment of surface and invasive mycoses caused by members of the genus Candida. The mechanism of action of azoles involves competitive binding to the cytochrome P450 family enzyme lanosterol 14 alpha-demethylase (cyp51A), which catalyzes the biosynthesis of ergosterol (a key component of the fungal cell wall). Nonsynonymous nucleotide substitutions of the ERG11 gene encoding lanosterol 14 alpha-demethylase of C. albicans lead to disruption of the enzyme's affinity to azoles and the acquisition of resistance by the micromycetes to antifungal drugs. We studied the genetic polymorphism of three original ERG11 sequences from clinical isolates of C. albicans. Some nonsynonymous substitutions of resistant isolates were related to amino acid residues involved in the interaction with posaconazole, itraconazole, voriconazole, and fluconazole. In the nucleotide alignment of 224 C. albicans ERG11 open reading frames from Genbank, a positive selection was found at 4 positions encoding amino acid residues 116 (Asp / Glu), 132 (Tyr / Phe / His), 266 (Glu / Asp ), 488 (Val / Ile). For the Сyp51А type sequence of C. albicans, a complete list of ligand binding sites was established for the first time, which can later be used to interpret the meaning of amino acid substitutions detected in clinical isolates.