Evaluating the Antifungal Potential of Autophagy-Related Protein 4 (ATG4) Inhibitors against Human Fungal Pathogens

ABSTRACT

Emerging fungal pathogens pose a significant threat to global public health. Despite the availability of antifungal agents, their clinical efficacy is increasingly challenged by the rise of fungicide-resistant strains. Therefore, identifying novel therapeutic targets and ensuring the safe application of antifungal agents are critical for advancing treatment strategies. Autophagy, a fundamental cellular process that maintains intracellular homeostasis by degrading and recycling dysfunctional proteins and organelles, is implicated in fungal pathogenicity. It indicates that inhibition of autophagy represents a promising approach for antifungal development. In this study, we evaluate the antifungal potential of autophagy inhibitors targeting the Autophagy-related protein 4 (ATG4)-mediated cleavage of Autophagy-related protein 8 (ATG8). Our findings demonstrate that ebselen and its analogs effectively inhibit ATG4 activity in Cryptococcus neoformans, Aspergillus fumigatus, and Aspergillus niger, exhibiting fungicidal activity against Cryptococcus and Candida species. These results provide valuable insights into novel antifungal development strategies, highlighting the therapeutic potential of autophagy inhibitors against diverse pathogenic fungi.