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

TL;DR

ETD151 is a promising antifungal peptide that works against both azole-sensitive and azole-resistant Aspergillus fumigatus strains without causing resistance.

Contribution

ETD151 shows antifungal activity against resistant A. fumigatus and targets glucosylceramides without inducing resistance.

Findings

ETD151 reduces A. fumigatus hyphal growth by 89% and metabolic activity by 70%.

ETD151 causes morphological changes in both azole-susceptible and -resistant strains.

ETD151 targets glucosylceramides and shows no cytotoxicity to human bronchial cells.

Abstract

•ETD151 is active against azole sensitive or resistant A. fumigatus clinical strains.•ETD151 targets glucosylceramides of the fungal membrane.•A. fumigatus does not develop resistance to ETD151.•ETD151 remains active in a model of A. fumigatus infected-bronchial epithelial cells.

ETD151 is active against azole sensitive or resistant A. fumigatus clinical strains.

ETD151 targets glucosylceramides of the fungal membrane.

A. fumigatus does not develop resistance to ETD151.

ETD151 remains active in a model of A. fumigatus infected-bronchial epithelial cells.

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 A. fumigatus clinical strains. Using cell-free in vitro 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 A. fumigatus. 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.

Image, graphical abstract

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