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Candida auris  is an emerging multi-drug resistant yeast that causes systemic infections. Here we show that  C .  auris  undergoes replicative aging (RA) that results from asymmetric cell division and causes phenotypic differences between mother and daughter cells similar to other pathogenic yeasts. Importantly, older  C .  auris  cells (10 generations) exhibited higher tolerance to fluconazole (FLC), micafungin, 5- flucytosine and amphotericin B compared to younger (0–3 generation) cells. Increased FLC tolerance was associated with increased Rhodamine 6G (R6G) efflux and therapeutic failure of FLC in a  Galleria  infection model. The higher efflux in the older cells correlated with overexpression of the efflux pump encoding gene  CDR1  (4-fold). In addition, 8-fold upregulation of the azole target encoding gene  ERG11  was noted in the older cells. Analysis of genomic DNA from older cells by qPCR indicates that transient gene duplication of  CDR1  and  ERG11  causes the observed age-dependent enhanced FLC tolerance in  C .  auris  strains. Furthermore, older cells exhibited a thickened cell wall, decreased neutrophil killing (24% vs 50%), increased epithelial cell adhesion (31.6% vs 17.8%) and upregulation of adhesin protein Als5p. Thus, this study demonstrates that transient gene duplication can occur during RA, causing increased FLC tolerance in old  C .  auris  cells.

Gene Duplication Associated with Increased Fluconazole Tolerance in Candida auris cells of Advanced Generational Age