Synergistic Antifungal Activity of Zinc Pyrithione and Nystatin against Multi-Drug-Resistant Candida (Candidozyma) auris: Evidence from In Vitro and In Vivo Models

Candida (Candidozyma) auris is a multidrug-resistant fungal pathogen that presents a growing global health concern due to its resistance to conventional antifungals. This study evaluated the antifungal potential of zinc pyrithione (ZnPT) and nystatin (NYS), both individually and in combination, against C. auris. Minimum inhibitory and fungicidal concentrations were determined, alongside assays for biofilm inhibition and eradication, including tests on porcine skin. Mechanistic evaluations included assessments of cell membrane integrity, efflux pump inhibition, and sorbitol protection. Safety was analyzed through hemocompatibility, the Ames test, and acute toxicity in Tenebrio molitor larvae. ZnPT + NYS combination had a synergistic antifungal effect, effectively inhibiting biofilm formation and increasing membrane permeability, as evidenced by protein leakage. No nucleotide leakage or mutagenic effects were observed, indicating low genotoxic risk. While ZnPT alone exhibited toxicity in T. molitor, the combination remained within safe limits. Overall, the ZnPT + NYS combination demonstrated strong antifungal and antibiofilm activity against C. auris, with favorable safety outcomes. These findings support further investigation into its clinical potential as a treatment strategy against this emerging pathogen.