Echinocandin Resistance in Candida auris Occurs in the Murine Gastrointestinal Tract Due to FKS1 Mutations

Abstract

Candida auris is resistant to multiple antifungal agents. This study investigated its antifungal susceptibility and explored FKS1 mutations across the isolates from mice enterically colonized with wild-type C. auris and treated with echinocandin. Resistant C. auris with FKS1 mutations, including S639F, S639Y, D642Y, R1354H, or R1354Y, were isolated and found to be micafungin- and caspofungin-resistant in vivo; however, the MICs of isolates with mutation in R1354 remained below the micafungin breakpoint in vitro.

Keywords: Candida auris; FKS1; antifungal resistance; echinocandins; gastrointestinal tract; yeast.

FIG 1

Survival analyses of mice infected with C. auris wild-type strain and FKS1 mutants. Immunocompromised mice were inoculated with C. auris NCPF 8971 (wild type [WT]) and isolates harboring FKS1 mutations. Micafungin (2.71 mg/kg) and caspofungin (0.76 mg/kg) were administered intraperitoneally for 7 consecutive days. The survival curves of FKS1 mutant infection were compared with those of FKS1 wild-type infection. The data were analyzed by log-rank (Mantel-Cox) test. Asterisks indicate statistically significant differences (*, P < 0.05). MFG, micafungin; CAS, caspofungin.

FIG 2

Treatment efficacy of micafungin and caspofungin against C. auris wild-type strain and FKS1 mutants. BALB/c mice were infected with C. auris NCPF 8971 (wild type) and isolates harboring FKS1 mutations. Micafungin (2.71 mg/kg) and caspofungin (0.76 mg/kg) were administered intraperitoneally for three consecutive days. The number of cells recovered from the bilateral kidneys is indicated for individual mice in the plots, and error bars represent SDs. Asterisks indicate statistically significant differences (**, P < 0.01), and ns indicates no significance (P > 0.05). NT, no treatment; MFG, micafungin; CAS, caspofungin.