In Silico Screening Identifies Pseudoprotodioscin as a Potential Antifungal Agent Against Multidrug-Resistant Candida auris

Candidozyma auris is an emerging multidrug-resistant fungal pathogen with very limited treatment options, posing a severe global threat. This study aimed to screen natural-product-derived inhibitors against multidrug-resistant C. auris. We compared transcriptomic datasets of drug-resistant and susceptible C. auris strains from public databases to identify shared differentially expressed genes across three distinct antifungal-resistance backgrounds. The pH-responsive gene 1 (PHR1) and lipase 1 (LIP1) were prioritized as molecular targets for further investigation. We then performed virtual screening from a natural-product library and applied molecular-dynamics simulations to assess target–ligand binding stability. Pseudoprotodioscin (PPD) and Corylifol A (CYA) were selected as candidate agents. Subsequent in vitro experiments were conducted to evaluate their antifungal potency. Our results showed that PPD exhibited promising antifungal activity and produced synergistic effects in combination with fluconazole. In conclusion, this study suggests that the natural product PPD obtained via computer-aided screening may underpin the development of innovative antifungals against multidrug-resistant C. auris.