Exploiting natural and nature-inspired siderophores to target ferroptosis in Pyricularia oryzae

Rice (Oryza sativa L.) serves as the primary staple food for more than half of the world’s population. Among the diseases affecting rice, blast—caused by Pyricularia oryzae—is the most devastating, leading to global yield losses estimated between 20% and 40%. The control of rice blast relies heavily on extensive fungicide applications, representing over 8% of the global fungicide market. Over the years, several classes of fungicides have been employed against P. oryzae, including strobilurins and demethylation inhibitors (DMIs). However, both classes act through single-site mechanisms, and the pathogen has progressively developed resistance to them. Consequently, the identification of novel molecular targets and the development of new chemical scaffolds are urgently needed to effectively manage this disease. In this context, modulation of ferroptosis—a recently characterized form of iron-dependent regulated cell death—has emerged as a promising strategy to interfere with fungal pathogenicity. In P. oryzae, ferroptosis initiates in the terminal conidial cell and subsequently spreads to the remaining two cells during appressorium formation and maturation; this process is essential for successful host infection. Notably, ferric ions (Fe3+) and not ferrous ions (Fe2+), play a key role in triggering ferroptosis in the pathogen. Herein, we report the synthesis and biological evaluation of natural (Figure 1) and nature-inspired catecholamide-based iron chelators (siderophores) as potential inhibitors of ferroptosis in P. oryzae.