Deciphering the Mrr1/Mdr1 Pathway in Azole Resistance of Candida auris

Abstract

Candida auris is an emerging yeast pathogen with a remarkable ability to develop antifungal resistance, in particular to fluconazole and other azoles. Azole resistance in C. auris was shown to result from different mechanisms, such as mutations in the target gene <i>ERG11</i> or gain-of-function (GOF) mutations in the transcription factor <i>TAC1b</i> and overexpression of the drug transporter Cdr1. The roles of the transcription factor Mrr1 and of the drug transporter Mdr1 in azole resistance is still unclear. Previous works showed that deletion of <i>MRR1</i> or <i>MDR1</i> had no or little impact on azole susceptibility of C. auris. However, an amino acid substitution in Mrr1 (N647T) was identified in most C. auris isolates of clade III that were fluconazole resistant. This study aimed at investigating the role of the transcription factor Mrr1 in azole resistance of C. auris. While the <i>MRR1</i>^N647T mutation was always concomitant to hot spot <i>ERG11</i> mutations, <i>MRR1</i> deletion in one of these isolates only resulted in a modest decrease of azole MICs. However, introduction of the <i>MRR1</i>^N647T mutation in an azole-susceptible C. auris isolate from another clade with wild-type <i>MRR1</i> and <i>ERG11</i> alleles resulted in significant increase of fluconazole and voriconazole MICs. We demonstrated that this <i>MRR1</i> mutation resulted in reduced azole susceptibility via upregulation of the drug transporter <i>MDR1</i> and not <i>CDR1</i>. In conclusion, this work demonstrates that the Mrr1-Mdr1 axis may contribute to C. auris azole resistance by mechanisms that are independent from <i>ERG11</i> mutations and from <i>CDR1</i> upregulation.