Targeting ferroptosis in Pyricularia oryzae by natural and nature-inspired siderophores

Rice (Oryza sativa L.) is the major staple food for more than 50% of world’s population. The rice-blast fungus, Pyricularia oryzae, represents a major threat to global rice production, between 20% and 40% yield annual losses, causing a significant economic damage. The management of the rice blast disease requires a massive application of fungicides, which accounts for more than 8% of total fungicide market.1 Diverse classes of fungicides, during the years, have been used against P. oryzae,2,3 including strobilurins and demethylation inhibitors (DMI).4 Both classes of antifungal compounds have a single-site mode of action and the fungal pathogen populations developed resistance to them. For this reason, the identification of new targets and the discovery of new scaffolds to combat the pathogen is urgently needed. Ferroptosis was recently described as a new form of a regulated, iron-dependent cell death, which plays a key role also during P. oryzae infection.5 Ferroptosis, in P. oryzae, starts from the terminal conidial cell, and then progresses to the other two cells during the appressorium formation and maturation, and this ferroptotic cell death is required for the infection. Herein, we present the synthesis and biological evaluation of natural (Figure 1) and nature-inspired iron chelators (siderophores), containing the catecholamide moiety, as potential inhibitors of ferroptosis in P. oryzae.