Polycatechol-based iron predators disrupt fungal iron homeostasis to drive selective antifungal action

Although cationic polymers emerge as promising antifungal candidates owing to structural tunability, design flexibility, and resistance to proteolytic degradation, their clinical utility has been hampered by non-selective membrane-disruption mechanisms. Herein, we develop a class of polycatechols- termed fungal iron predators (FIPs), exhibit exceptional fungicidal activity and markedly low cytotoxicity.

These FIPs can efficiently infiltrate fungal cells, selectively sequester labile irons, and disrupt iron homeostasis and metabolism. The ensuing iron starvation provokes severe mitochondrial dysfunction and energy collapse, culminating in fungal cell death. Through systemic optimization of cationic density and catechol stoichiometry, we obtained an FIP variant demonstrating potent antifungal activity with high selectivity toward fungi over mammalian cells, minimal propensity to induce resistance, and supplementary antioxidant properties.