Cell Wall-Mediated Antifungal Activity of the Aqueous Extract of Hedera helix L. Leaves Against Diplodia corticola

<b>Background/Objectives:</b> Cork oak forests have been declining due to fungal pathogens such as <i>Diplodia corticola</i>. However, the preventive fungicides against this fungus have restricted use due to the deleterious effects on human health and the environment, prompting the need for sustainable alternatives. Here, we describe the antifungal activity of an aqueous extract of <i>Hedera helix</i> L. leaves (HAE) against <i>D. corticola</i> and the possible mechanism of action. <b>Results/Methods:</b> The chemical analysis revealed compounds like the saponin hederacoside C, quinic acid, 5-<i>O</i>-caffeoylquinic acid, rutin, and glycoside derivatives of quercetin and kaempferol, all of which have been previously reported to possess antimicrobial activity. Remarkable in vitro antifungal activity was observed, reducing radial mycelial growth by 70% after 3 days of inoculation. <i>Saccharomyces cerevisiae</i> mutants, <i>bck1</i> and <i>mkk1</i>/<i>mkk2,</i> affected the cell wall integrity signaling pathway were more resistant to HAE than the wild-type strain, suggesting that the extract targets kinases of the signaling pathway, which triggers toxicity. The viability under osmotic stress with 0.75 M NaCl was lower in the presence of HAE, suggesting the deficiency of osmotic protection by the cell wall. <b>Conclusions:</b> These results suggest that ivy extracts can be a source of new natural antifungal agents targeting the cell wall, opening the possibility of preventing fungal infections in cork oaks and improving the cork production sector using safer and more sustainable approaches.