Combating Fungal Infections and Resistance with a Dual-Mechanism Luminogen to Disrupt Membrane Integrity and Induce DNA Damage

Antifungal drug resistance is a critical concern, demanding innovative therapeutic solutions. The dual-targeting mechanism of action (MoA), as an effective strategy to reduce drug resistance, has been validated in the design of antibacterial agents. However, the structural similarities between mammalian and fungal cells complicate the development of such a strategy for antifungal agents as the selectivity can be compromised. Herein, we introduce a dual-targeting strategy addressing fungal infections by selectively introducing DNA binding molecules into fungal nuclei. We incorporate rigid hydrophobic units into a DNA-binding domain to fabricate antifungal luminogens of TPY and TPZ, which exhibit enhanced membrane penetration and DNA-binding capabilities. These compounds exhibit dual-targeting MoA by depolarizing fungal membranes and inducing DNA damage, amplifying their potency against fungal pathogens with undetectable drug resistance. TPY and TPZ demonstrated robust antifungal activity in vitro and exhibited ideal therapeutic efficacy in a murine model of <i>C. albicans</i>-induced vaginitis. This multifaceted approach holds promise for overcoming drug resistance and advancing antifungal therapy.