Atazanavir Resensitizes Candida auris to Azoles

Abstract

Candida auris represents an urgent health threat. Here, we identified atazanavir as a potent drug capable of resensitizing C. auris clinical isolates to the activity of azole antifungals. Atazanavir was able to significantly inhibit the efflux pumps, glucose transport, and ATP synthesis of all tested isolates of C. auris. In addition, the combination of itraconazole with atazanavir-ritonavir significantly reduced the burden of azole-resistant C. auris in murine kidneys by 1.3 log₁₀ (95%), compared to itraconazole alone.

Keywords: Candida auris; HIV protease inhibitors; atazanavir; azole resistance; efflux pumps; in vivo disseminated candidiasis mouse model.

FIG 1

(A) Time-kill curve of itraconazole (ITC) at 0.5 μg/mL, atazanavir (ATV) at 16 μg/mL, or a combination of both (ITC+ATV). The drugs were assessed against C. auris AR0390 for 48 h at 35°C. (B) Scanning images of C. auris AR0390 colonies from the 24-hour time point plated onto YPD agar plates and incubated for 24 hours.

FIG 2

Effect of atazanavir (ATV) on Nile red efflux, glucose utilization, and ATP content of C. auris isolates. (A) Effect of ATV on efflux of Nile red in five C. auris clinical isolates. Asterisks (*) denote a statistical difference (P < 0.05) between the untreated and ATV-treated C. auris cells in the intensity of Nile red fluorescence. (B) Effect of ATV on glucose utilization of C. auris. Asterisks (*) represent a statistical difference (P < 0.0001) in the percent change in optical density at 590 nm (OD₅₉₀) between ATV-treated cells and the untreated control, as determined by the unpaired t test. (C) Effect of ATV against C. auris ATP content. Asterisks (*) represent a statistical difference (P < 0.0001) in ATP levels between ATV-treated and untreated cells, as determined by the unpaired t test.

FIG 3

In vivo efficacy of the itraconazole (ITC)-atazanavir (ATV)-ritonavir (RTV) combination in a murine model of C. auris disseminated infection. Female CD-1 mice (n = 8) were infected with azole-resistant C. auris AR0390 and then treated with either the vehicle control, ITC (5 mg/kg), ATV-RTV (90 and 30 mg/kg, respectively), or ITC-ATV-RTV (5, 90, and 30 mg/kg, respectively). Statistical difference was measured via one-way analysis of variance (ANOVA) with the post hoc Dunnett’s test for multiple comparisons. The asterisk (*) denotes statistical significance of the combination treatment (P < 0.01) compared to the untreated control. The pound sign (#) denotes statistical significance (P < 0.01) compared to the ITC-treated group.