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. 2022 Nov 1;44(11):5379-5389.
doi: 10.3390/cimb44110364.

Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study

Juliana de C Fenley  1 , Patrícia P de Barros  1   2 , Paulo H F do Carmo  1 , Maíra T Garcia  1 , Rodnei D Rossoni  1 , Juliana C Junqueira  1
Affiliations

Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study

Juliana de C Fenley et al. Curr Issues Mol Biol. .

Abstract

Candida albicans is the chief etiological agent of candidiasis, a mycosis prevalent in individuals with acquired immunodeficiency syndrome (AIDS). In recent years, the introduction of human immunodeficiency virus (HIV) protease inhibitors (HIV-PI) has reduced the prevalence of candidiasis in these patients. Seeking new therapeutic strategies based on the perspective of drug repositioning, we evaluated the effects of two second-generation HIV-PIs, atazanavir (ATV) and darunavir (DRV), on virulence factors of C. albicans and experimental candidiasis. For this, clinical strains of C. albicans were subjected to in vitro and in vivo treatments with ATV or DRV. As a result, ATV and DRV exhibited antifungal activity against fungal cells at 512 μg/mL, reduced the viability and biomass of biofilms, and inhibited filamentation of C. albicans. In addition, these HIV-PIs downregulated the expression of SAP2 and BRC1 genes of C. albicans. In an in vivo study, prophylactic use of ATV and DRV prolonged the survival rate of Galleria mellonella larvae infected with C. albicans. Therefore, ATV and DRV showed activity against C. albicans by reducing cell growth, biofilm formation, filamentation, and expression of virulence genes. Furthermore, ATV and DRV decreased experimental candidiasis, suggesting the repurposing of HIV-PIs as antifungal treatments for C. albicans infections.

Keywords: Candida albicans; HIV; atazanavir sulfate; darunavir; protease inhibitors; virulence factors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
ATV and DRV reduced the viability and biomass of Candida albicans biofilms. Fungal viability of biofilms of (A) C. albicans 60 (Ca60) and (B) C. albicans 70 (Ca70) not treated (NT) and treated with fluconazole (FCZ), darunavir (DRV), and atazanavir (ATV). Biofilm biomass of (C) Ca60 and (D) Ca70 without treatment (NT) and after treatment with FCZ, DRV, and ATV. Results represent the mean of three replicates. FCZ: fluconazole; DRV: darunavir; ATV: atazanavir; NT = not treated; NG = no growth. Different letters (A, B, C, D) indicate significant differences (p < 0.05).
Figure 2
Figure 2
ATV and DRV decreased the number of C. albicans filaments. Scores attributed for hyphae formation of (A) C. albicans 60 (Ca60) and (B) C. albicans 70 (Ca70) not treated (NT) and treated with darunavir (DRV) and atazanavir (ATV). Results represent the mean of three replicates. DRV: darunavir; ATV: atazanavir; NT = not treated. Different letters (A, B) indicate significant differences (p < 0.05).
Figure 3
Figure 3
Relative expression of C. albicans genes. Relative quantification of BCR1 and SAP2 genes for Ca70 biofilms non-treated (NT) and treated with darunavir (DRV) and atazanavir (ATV). Normalization was performed using the RIP1 gene. DRV and ATV treatments were compared with NT using the student’s t-test (p < 0.05).
Figure 4
Figure 4
ATV and DRV increased the survival of G. mellonella infected with C. albicans strains. Survival curve of uninoculated G. mellonella larvae (no injection), infected with (A,C) C. albicans 60 and (B,D) C. albicans 70 and treated with PBS, atazanavir (ATV), or darunavir (DRV). Larvae were pre-treated with ATV or DRV at the last left proleg and infected with C. albicans at the last right proleg. Ca60: C. albicans 60; Ca70: C. albicans 70; DRV: darunavir; ATV: atazanavir. p < 0.05.
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