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
Sveva Pelliccia, Pasquale Russomanno, Simona Barone, B Botella Mateu, Antonella Ilenia Alfano, Martina Miranda, Lorena Coretti, Francesca Lembo, Marialuisa Piccolo, Carlo Irace, Laura Friggeri, Tatiana Y. Hargrove, Aaron Curtis, Galina I. Lepesheva, Kevin Kavanagh, Elisabetta Buommino, Margherita Brindisi
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. In vivo studies using a Galleria mellonella model confirmed the previously in vitro observed synergistic effect of 5b with voriconazole. Also considering its biocompatibility in a cellular model of human keratinocytes, these results indicate that 5b represents a promising compound for a further optimization campaign.