Farnesol Boosts the Antifungal Effect of Fluconazole and Modulates Resistance in Candida auris through Regulation of the CDR1 and ERG11 Genes

Abstract

<i>Candida auris</i> is considered a serious fungal pathogen frequently exhibiting a high resistance to a wide range of antifungals. In this study, a combination of the quorum-sensing molecule farnesol (FAR) and fluconazole (FLU) was tested on FLU-resistant <i>C. auris</i> isolates (<i>C. auris</i> S and <i>C</i>. <i>auris</i> R) compared to the susceptible <i>C. auris</i> H261. The aim was to assess the possible synergy between FAR and FLU, by reducing the FLU minimal inhibitory concentration, and to determine the mechanism underlying the conjunct effect. The results confirmed a synergic effect between FAR and FLU with a calculated FIC index of 0.75 and 0.4 for <i>C. auris</i> S and <i>C. auris</i> R, respectively. FAR modulates genes involved in azole resistance. When FAR was added to the cells in combination with FLU, a significant decrease in the expression of the <i>CDR1</i> gene was observed in the resistant <i>C. auris</i> isolates. FAR seems to block the Cdr1 efflux pump triggering a restoration of the intracellular content of FLU. These results were supported by observed increasing accumulation of rhodamine 6G by <i>C. auris</i> cells. Moreover, <i>C. auris</i> treated with FAR showed an <i>ERG11</i> gene down-regulation. Overall, these results suggest that FAR is an effective modulator of the Cdr1 efflux pump in <i>C. auris</i> and, in combination with FLU, enhances the activity of this azole, which might be a promising strategy to control infections caused by azole-resistant <i>C. auris.</i>