Fungal infections represent a significant global health concern, with a growing prevalence of antifungal drug resistance. Targeting glucosylceramides (GlcCer), which are functionally essential glycosphingolipids present in fungal membranes, represents a promising strategy for the development of new antifungals.

GlcCer are associated with the antifungal activity of certain antimicrobial peptides present in plants and insects, and named defensins. The 44-residue ETD151 peptide, optimized from butterfly defensins, is active against a range of fungal pathogens of interest to human health or agriculture. For example, we previously showed that ETD151 induce a multifaceted mechanism of action (MOA) in Botrytis cinerea, a multi-resistant phytopathogenic fungus used as model (Aumer et al. 2020).

This multifaceted MOA makes ETD151 a promising candidate for combating fungal resistance. Here, we took up the challenge of identifying its molecular target. We have shown that the ETD151 peptide binds at the molecular level to GlcCer and localizes preferentially to the membrane, where it induces various toxic effects. Identifying its molecular target and understanding the MOA of ETD151 pave the way for new perspectives in human health and crop protection.

Reference :
O. Kharrat, Y. Yamaryo-Botté, R. Nasreddine, S. Voisin, T. Aumer, B.P.A. Cammue, J. Madinier, T. Knobloch, K. Thevissen, R. Nehmé, V. Aucagne, C. Botté, P. Bulet, & C. Landon.
The antimicrobial activity of ETD151 defensin is dictated by the presence of glycosphingolipids in the targeted organisms.
Proc. Natl. Acad. Sci. U.S.A. (2025) 122 (7) e2415524122, https://doi.org/10.1073/pnas.2415524122.