Novel <i>ERG11</i> and <i>TAC1b</i> Mutations Associated with Azole Resistance in Candida auris

Abstract

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