Antifungal activity of ETD151 against azole-susceptible and -resistant Aspergillus fumigatus clinical isolates

Aspergillus fumigatus is an opportunistic pathogen responsible for a wide spectrum of severe diseases, depending on the host's immune status. Current therapeutic options against this fungus are limited, and the emergence of resistance against azole derivatives, which are the first-line therapy, regardless of the clinical form, poses serious clinical challenges. Antimicrobial peptides, now used routinely, are valuable alternatives to conventional antibiotics for treating certain bacterial infections. In this study, we investigated the antifungal potential of ETD151, a synthetic peptide, against <i>A. fumigatus</i> clinical strains. Using cell-free <i>in vitro</i> assays and primary human bronchial epithelial cell (PHBEC) infection models, we demonstrated that ETD151 significantly reduces A. fumigatus hyphal growth by 89 % and metabolic activity by 70 %. This was associated with marked morphological alterations that occurred both in azole-susceptible and azole-resistant strains. Rescue assay and analysis of a glucosylceramide-deficient strain revealed that those sphingolipids are a molecular target of ETD151 in <i>A. fumigatus</i>. Importantly, ETD151 showed no cytotoxicity toward PHBECs and maintained its antifungal activity in co-culture conditions. These findings support the potential of ETD151 as a promising antifungal candidate for the treatment of A. fumigatus-associated diseases.