Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species

• Published in: Memórias do Instituto Oswaldo Cruz Vol. 111; no. 3; pp. 192 - 199
• Main Authors: Silva, Danielly Beraldo dos Santos, Rodrigues, Luana Mireli Carbonera, Almeida, Adriana Araújo de, Oliveira, Kelly Mari Pires de, Grisolia, Alexéia Barufatti
• Format: Journal Article
• Language: English
• Published: Brazil Fundação Oswaldo Cruz, Fiocruz 01-03-2016; Instituto Oswaldo Cruz, Ministério da Saúde; Fundação Oswaldo Cruz (FIOCRUZ)
• Subjects: 14α-demethylase; Antifungal Agents - pharmacology; Azoles - pharmacology; Candida - classification; Candida - drug effects; Candida - genetics; Candida - isolation & purification; Candida glabrata - genetics; Candida krusei; Dose-Response Relationship, Drug; Drug Resistance, Fungal - genetics; Genes, Fungal; Haplotypes - drug effects; Humans; Microbial Sensitivity Tests; PARASITOLOGY; Phylogeny; Point Mutation - drug effects; Sterol 14-Demethylase - genetics; TROPICAL MEDICINE; voriconazole; Voriconazole - pharmacology; Y166S; yeasts; yeasts; Candida krusei; voriconazole; 14α-demethylase; Y166S
• ISSN: 1678-8060; 0074-0276; 1678-8060
• DOI: 10.1590/0074-02760150400

The azoles are the class of medications most commonly used to fight
infections caused by Candida sp. Typically, resistance can be
attributed to mutations in ERG11 gene (CYP51) which encodes the
cytochrome P450 14α-demethylase, the primary target for the
activity of azoles. The objective of this study was to identify
mutations in the coding region of the ERG11 gene in clinical isolates
of Candida known to be resistant to azoles. We identified three new
synonymous mutations in the ERG11 gene in the isolates of Candida
glabrata (C108G, C423T and A1581G) and two new nonsynonymous
mutations in the isolates of Candida krusei - A497C (Y166S) and
G1570A (G524R). The functional consequence of these nonsynonymous
mutations was predicted using evolutionary conservation scores. The
G524R mutation did not have effect on 14α-demethylase
functionality, while the Y166S mutation was found to affect the enzyme.
This observation suggests a possible link between the mutation and
dose-dependent sensitivity to voriconazole in the clinical isolate of
C. krusei. Although the presence of the Y166S in phenotype of reduced
azole sensitivity observed in isolate C. krusei demands investigation,
it might contribute to the search of new therapeutic agents against
resistant Candida isolates.