Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases · 2025
Relative contributions of the ERG11VF125AL and MRR1AN647T mutations to fluconazole resistance in Clade III Candidozyma (Candida) auris clinical isolates.
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Barker Katherine S, Zhang Qing, Peters Tracy L, Rybak Jeffrey M, Morschhäuser Joachim, Cuomo Christina A, Rogers P David
Аннотация
OBJECTIVES: Candidozyma (Candida) auris is an emerging fungal pathogen of global concern that often exhibits multidrug resistance. Of the six described C. auris clades, Clade III has been found to be nearly universally fluconazole resistant, and almost every Clade III isolate described carries a mutation leading to a VF125AL substitution in ERG11, the gene encoding the fluconazole target lanosterol 14α-demethylase, and a mutation leading to a N647T substitution in the gene encoding Mrr1a, a transcriptional regulator of the Mdr1 transporter. In this study, we aimed to determine the specific contributions of these mutations to triazole antifungal susceptibility in Clade III C. auris isolates.
METHODS: We introduced the Clade III MRR1A mutation into a Clade I background using CRISPR-Cas9 gene editing. In two Clade III clinical isolates, we corrected the native MRR1A and ERG11 mutations to their wild-type sequences, as well as disrupted MDR1. Triazole susceptibilities and MDR1 gene expression were measured in all strains.
RESULTS: Introduction of the N647T substitution in a Clade I background increases fluconazole MIC from 2 to 4 μg/mL. Correction of MRR1A or disruption of MDR1 in each Clade III background resulted in a one-dilution decrease in fluconazole MIC (64-32 μg/mL), whereas the ERG11 correction resulted in a three-to four-dilution decrease (64 to 4-8 μg/mL) in fluconazole MIC. Correction of both mutations together resulted in a further decrease to 4 μg/mL. Similar changes were observed for voriconazole.
CONCLUSIONS: Our findings show that although the MRR1A mutation makes a modest contribution, the ERG11 mutation is responsible for most of the fluconazole resistance observed in Clade III isolates. We also show that although these mutations likewise affect voriconazole susceptibility, they have no effect on itraconazole, isavuconazole, or posaconazole susceptibility, suggesting the therapeutic utility of these antifungals for infections due to Clade III C. auris isolates.
METHODS: We introduced the Clade III MRR1A mutation into a Clade I background using CRISPR-Cas9 gene editing. In two Clade III clinical isolates, we corrected the native MRR1A and ERG11 mutations to their wild-type sequences, as well as disrupted MDR1. Triazole susceptibilities and MDR1 gene expression were measured in all strains.
RESULTS: Introduction of the N647T substitution in a Clade I background increases fluconazole MIC from 2 to 4 μg/mL. Correction of MRR1A or disruption of MDR1 in each Clade III background resulted in a one-dilution decrease in fluconazole MIC (64-32 μg/mL), whereas the ERG11 correction resulted in a three-to four-dilution decrease (64 to 4-8 μg/mL) in fluconazole MIC. Correction of both mutations together resulted in a further decrease to 4 μg/mL. Similar changes were observed for voriconazole.
CONCLUSIONS: Our findings show that although the MRR1A mutation makes a modest contribution, the ERG11 mutation is responsible for most of the fluconazole resistance observed in Clade III isolates. We also show that although these mutations likewise affect voriconazole susceptibility, they have no effect on itraconazole, isavuconazole, or posaconazole susceptibility, suggesting the therapeutic utility of these antifungals for infections due to Clade III C. auris isolates.