The haploinsufficiency profile of α-hederin suggests a caspofungin-like antifungal mode of action.

The leaves of common ivy (Hedera helix) contain the cytotoxic saponin α-hederin, which is inhibitory to Candida albicans at low concentrations. To investigate the mode of action of α-hederin, a haploinsufficiency screen was carried out using a library of 1152 Saccharomyces cerevisiae deletion strains. An ethanol ivy extract containing α-hederin was used in the initial screen to reduce the amount of compound required. Strains exhibiting disproportionately low growth were then examined in more detail by comparing growth curves in the presence and absence of α-hederin. This approach identified three hypersensitive strains carrying gene deletions for components of the transcription related proteins SWI/SNF, RNA polymerase II and the RSC complex. Saponin cytotoxicity is often attributed to membrane damage, however α-hederin did not induce hypersensitivity with an aminophospholipid translocase deletion strain that is frequently hypersensitive to membrane damaging agents. The haploinsufficiency profile of α-hederin is most similar to that reported for drugs such as caspofungin that inhibit synthesis of the fungal cell wall. Screening with plant extracts rather than isolated compounds, provides a valuable shortcut in haploinsufficiency screening provided hypersensitive strains are then confirmed as such using purified active principles.
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