Hydroxytyrosol (HT) Analogs Act as Potent Antifungals by Direct Disruption of the Fungal Cell Membrane

Fungal infections constitute an emerging threat and a prevalent health problem due to increasing number of immunocompromised people and pharmacological or other treatments aiming at viral infections, cancer or allergies. Currently used antifungals suffer from inefficiency, toxic side effects and developing drug-resistance. Additionally, over the last two decades no new classes of antifungals have been approved, emphasizing the urgent need for developing a novel generation of antifungals. Here, we investigate the antifungal activity of a series of chemically synthesized Hydroxytyrosol (HT) analogs. HT is one of the major phenolic compounds in olive oil, shown to possess radical-scavenging antioxidant, antiproliferative, proapoptotic and anti-inflammatory activities. No previous report has studied HT analogs as antifungals. We show that specific analogs have broad and strong antifungal activity, significantly stronger than the parent compound HT. Using Aspergillus nidulans as an in vivo cellular model system, we show that antifungal HT analogs have an unprecedented efficiency in fungal plasma membrane destruction. Importantly, antifungal HT analogs did not show toxicity in a mammalian cell line, whereas no resistance to HT analogs was obtained by standard mutagenesis. Our results open the way for the development of a novel, efficient and safer class of antifungals.