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

ABSTRACT: 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 14?-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candida species 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 14?-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.

SUBMITTER: Silva DB

PROVIDER: S-EPMC4804502 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Silva Danielly Beraldo dos Santos DB Rodrigues Luana Mireli Carbonera LM Almeida Adriana Araújo de AA Oliveira Kelly Mari Pires de KM Grisolia Alexéia Barufatti AB

Memorias do Instituto Oswaldo Cruz 20160315 3

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 theERG11 gene in clinical isolates of Candida species known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gen ...[more]

PMID: 26982177

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Project description:Background and purposeCandidiasis is referred to a group of superficial and deep-tissue fungal infections often caused by Candida albicans. The superficial infections affect the oral, oropharynx, esophagus, and vaginal mucosa. The treatment of choice for these infections is the use of azoles, such as fluconazole. However, the increased use of these antifungal agents has led to the emergence of azole-resistant isolates of C. albicans. Different mechanisms have been suggested for the development of drug resistance, such as mutations in the encoding gene ERG11. Mutations in ERG11 result in changes in the ERG11p spatial construction and reduce the affinity between the protein and azole. This study aimed to determine the susceptibility profile of C. albicans clinical isolates to fluconazole using microdilution method. The present research was also targeted toward the detection of mutations that might be related to fluconazole resistance by the amplification and sequencing of ERG11 gene.Materials and methodsThis study was conducted on a total of 216 clinical isolates obtained from Mashhad, Isfahan, and Tehran cities in Iran, during 2016-2018. The clinical isolates were identified using molecular techniques. Furthermore, minimum inhibitory concentration (MICs) was determined according to the clinical and laboratory standards institute M27-A3 and M27-S4 documents. The concentration range for fluconazole was obtained as 0.063-64 μg/ml. In the resistant strains, ERG11 genes were amplified by specific primers. Subsequently, cycle sequencing reactions were performed on purified polymerase chain reaction (PCR) products in forward and reverse directions. Finally, the results were analyzed by MEGA (version 7) and Gene Runner software (version 6.5.30).ResultsOut of 216 strains, 100 (46.3%) species were identified as C. albicans. The MIC values for fluconazole had a range of 0.125-16 μg/ml with the MIC50 and MIC90 values of 0.5 and 1 μg/ml, respectively. Totally, 41 nucleotide changes were detected among 4 resistant isolates. In this regard, 4 out of 41 mutations in codons caused changes in ERG11p; however, these mutations did not lead to fluconazole resistance.ConclusionFluconazole resistance among clinical isolates is not merely due to the changes in ERG11p. This resistance may be also related to some other mechanisms, such as the prevention of the intracellular accumulation of the antifungal agent and alteration of the target enzyme to diminish drug binding.

Dataset Information

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

Publications

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

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