A First-in-Class Pyrazole-isoxazole Enhanced Antifungal Activity of Voriconazole: Synergy Studies in an Azole-Resistant <i>Candida albicans</i> Strain, Computational Investigation and in Vivo Validation in a <i>Galleria mellonella</i> Fungal Infection Model.

ABSTRACT: The widespread and irrational use of azole antifungal agents has led to an increase of azole-resistant Candida albicans strains with an urgent need for combination drug therapy, enhancing the treatment efficacy. Here, we report the discovery of a first-in-class pyrazole-isoxazole, namely, 5b, that showed remarkable growth inhibition against the C. albicans ATCC 10231 strain in combination with voriconazole, acting as a downregulator of ERG 11 (Cyp51) gene expression with a significant reduction of the yeast-to-hypha morphological transition. Furthermore, C. albicans CYP51 enzyme assay and in-depth molecular docking studies unveiled the unique ability of the combination of 5b and voriconazole to completely fill the CYP51 binding sites.

SUBMITTER: Pelliccia S 

PROVIDER: S-EPMC11482282 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature