Novel ERG11 and TAC1b Mutations Associated with Azole Resistance in Candida auris

Candida auris is a novel Candida species that has spread in all continents, causing nosocomial outbreaks of invasive candidiasis. C. auris has the ability to develop resistance to all antifungal drug classes. Notably, many C. auris isolates are resistant to the azole drug fluconazole, a standard therapy for invasive candidiasis. Azole resistance in C. auris can result from mutations in the azole target gene ERG11 and/or overexpression of the efflux pump Cdr1. TAC1 is a transcription factor controlling CDR1 expression in C. albicans. The role of TAC1 homologs in C. auris (TAC1a and TAC1b) remains to be better defined. In this study, we compared sequences of ERG11, TAC1a, and TAC1b between a fluconazole-susceptible and five fluconazole-resistant C. auris isolates of clade IV. Among four of the resistant isolates, we identified similar genotypes with concomitant mutations in ERG11 (F444L) and TAC1b (S611P). The simultaneous deletion of tandemly arranged TAC1a/TAC1b resulted in a decrease of MIC for fluconazole. Introduction of the ERG11 and TAC1b mutations separately and/or combined in the wild-type azole-susceptible isolate resulted in a significant increase of azole resistance with a cumulative effect of the two combined mutations. Interestingly, CDR1 expression was not significantly affected by TAC1a/TAC1b deletion or by the presence of the TAC1b S611P mutation, suggesting the existence of Tac1-dependent and Cdr1-independent azole resistance mechanisms. In conclusion, we demonstrated the role of two previously unreported mutations responsible for azole resistance in C. auris, which were a common signature among four azole-resistant isolates of clade IV.

Automated summary

Candida auris is a novel Candida species with global spread and multidrug resistance. This study identified two previously unreported mutations in ERG11 and TAC1b genes, which were found to be associated with fluconazole resistance. Further research is needed to better understand the mechanisms underlying these mutations in azole resistance.