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.
Soil bacteria that can form nitrogen-fixing symbiotic nodules on legumes, collectively called rhizobacteria or rhizobia, have a global impact on the sustainable agriculture and the cycling of nitrogen in the biosphere. In the symbiotic nodules, rhizobia are differentiated to organelle-like bacteroids, which populate the infected plant cells and specialize in reducing the atmospheric nitrogen to ammonium. The efficiency of this process depends on many factors, a central one being the proper exchange of metabolites and ions between the two symbionts to allow integration of metabolism in the symbiotic nodule. This exchange is mediated by the membrane transporters of both rhizobial and plantal origin. A few well-known transporters are used in all types of symbiotic nitrogen fixation to transport dicarboxylic acids from the plant to rhizobium (to feed the TCA cycle) and reduced (fixed) nitrogen, mostly as ammonia, from the rhizobium to the plant. Apart from these unequivocally needed transporters, distinct groups of rhizobia and legume symbionts can use additional important metabolite transporters most of which remain unstudied to date (
Key words: fungal pathogens/Aspergillus nidulans/plasma membrane/antimicrobial/resistance 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) analogues. ΗΤ 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 analogues as antifungals. We show that specific analogues have broad and strong antifungal activity, significantly stronger than the parent compound HT. Using A. nidulans as an in vivo cellular model system, we show that antifungal HT analogues have an unprecedented efficiency in fungal plasma membrane destruction. Importantly, antifungal HT analogues did not show toxicity in a mammalian cell line, whereas no resistance to HT analogues was obtained by standard mutagenesis. Our results open the way for the development of a novel, efficient and safer class of antifungals.
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