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

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.

Galleria mellonella experimental model for bat fungal pathogen Pseudogymnoascus destructans and human fungal pathogen Pseudogymnoascus pannorum.

Laboratory investigations of the pathogenesis of Pseudogymnoascus destructans, the fungal causal agent of bat White Nose Syndrome (WNS), presents unique challenges due to its growth requirements (4°-15°C) and a lack of infectivity in the current disease models. Pseudogymnoascus pannorum is the nearest fungal relative of P. destructans with wider psychrophilic - physiological growth range, and ability to cause rare skin infections in humans. Our broad objectives are to create the molecular toolkit for comparative study of P. destructans and P. pannorum pathogenesis. Towards these goals, we report the successful development of an invertebrate model in the greater wax moth Galleria mellonella. Both P. destructans and P. pannorum caused fatal disease in G. mellonella and elicited immune responses and histopathological changes consistent with the experimental disease.

A phenylthiazole derivative demonstrates efficacy on treatment of the cryptococcosis & candidiasis in animal models.

AIM: In this work we test 2-(2-(cyclohexylmethylene)hydrazinyl)-4-phenylthiazole (CHT) against Cryptococcus spp. and Candida albicans. METHODS: The ability of CHT to act in biofilm and also to interfere with C. albicans adhesion was evaluated, as well as the efficiency of the CHT in cryptococcosis and candidiasis invertebrate and murine models. RESULTS & CONCLUSION: In the present work we verified that CHT is found to inhibit Cryptococcus and C. albicans affecting biofilm in both and inhibited adhesion of Candida to human buccal cells. When we evaluated in vivo, CHT prolonged survival of Galleria mellonella after infections with Cryptococcusgattii, Cryptococcusneoformans or C. albicans and promoted a reduction in the fungal burden to the organs in the murine models. These results demonstrate CHT therapeutic potential.