Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 17;67(5):e0163122.
doi: 10.1128/aac.01631-22. Epub 2023 Apr 24.

Atazanavir Resensitizes Candida auris to Azoles

Yehia Elgammal  1   2 , Ehab A Salama  1   2 , Mohamed N Seleem  1   2
Affiliations

Atazanavir Resensitizes Candida auris to Azoles

Yehia Elgammal et al. Antimicrob Agents Chemother. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1
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
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
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.
See this image and copyright information in PMC

References

    1. Jeffery-Smith A, Taori SK, Schelenz S, Jeffery K, Johnson EM, Borman A, Manuel R, Brown CS, Candida auris Incident Management Team . 2018. Candida auris: a review of the literature. Clin Microbiol Rev 31:e00029-17. doi:10.1128/CMR.00029-17. - DOI - PMC - PubMed
    1. Robbins N, Caplan T, Cowen LE. 2017. Molecular evolution of antifungal drug resistance. Annu Rev Microbiol 71:753–775. doi:10.1146/annurev-micro-030117-020345. - DOI - PubMed
    1. Eldesouky HE, Lanman NA, Hazbun TR, Seleem MN. 2020. Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris, and displays potent synergistic interactions with azole drugs. Virulence 11:1466–1481. doi:10.1080/21505594.2020.1838741. - DOI - PMC - PubMed
    1. Kean R, Ramage G. 2019. Combined antifungal resistance and biofilm tolerance: the global threat of Candida auris. mSphere 4:e00458-19. doi:10.1128/mSphere.00458-19. - DOI - PMC - PubMed
    1. Mohammad H, Eldesouky HE, Hazbun T, Mayhoub AS, Seleem MN. 2019. Identification of a phenylthiazole small molecule with dual antifungal and antibiofilm activity against Candida albicans and Candida auris. Sci Rep 9:18941. doi:10.1038/s41598-019-55379-1. - DOI - PMC - PubMed

Publication types