Combating Fungal Infections\nand Resistance with a\nDual-Mechanism Luminogen to Disrupt Membrane Integrity and Induce\nDNA Damage

Antifungal drug resistance is a critical concern, demanding\ninnovative\ntherapeutic solutions. The dual-targeting mechanism of action (MoA),\nas an effective strategy to reduce drug resistance, has been validated\nin the design of antibacterial agents. However, the structural similarities\nbetween mammalian and fungal cells complicate the development of such\na strategy for antifungal agents as the selectivity can be compromised.\nHerein, we introduce a dual-targeting strategy addressing fungal infections\nby selectively introducing DNA binding molecules into fungal nuclei.\nWe incorporate rigid hydrophobic units into a DNA-binding domain to\nfabricate antifungal luminogens of TPY and TPZ, which exhibit enhanced\nmembrane penetration and DNA-binding capabilities. These compounds\nexhibit dual-targeting MoA by depolarizing fungal membranes and inducing\nDNA damage, amplifying their potency against fungal pathogens with\nundetectable drug resistance. TPY and TPZ demonstrated robust antifungal\nactivity in vitro and exhibited ideal therapeutic efficacy in a murine\nmodel of C. albicans-induced vaginitis.\nThis multifaceted approach holds promise for overcoming drug resistance\nand advancing antifungal therapy.