Novel antimicrobial peptide DvAMP serves as a promising antifungal agent against Cryptococcus neoformans.

Cryptococcus neoformans is an important opportunistic human fungal pathogen that causes cryptococcosis in immunocompromised patients. However, the number of drugs for the treatment of cryptococcosis is restricted, and the development of novel antifungal drugs and innovative strategies for the treatment of cryptococcosis is urgently needed. In this study, we validated that DvAMP is a novel antimicrobial peptide with antimicrobial activity and that it was obtained by pre-screening from the UniProt database of more than three million unknown functional sequences based on the quantitative structure-activity relationships (QSARs) protocol (http://www.chemoinfolab.com/antifungal). The peptide exhibited satisfactory biosafety and physicochemical properties, and relatively rapid fungicidal activity against C. neoformans. Meanwhile, DvAMP was able to inhibit the static biofilm of C. neoformans and cause a reduction in the thickness of the capsule. In addition, DvAMP exerts antifungal effects through membrane-mediated mechanisms (membrane permeability and depolarization) and mitochondrial dysfunction, involving a hybrid multi-hit mechanism. Furthermore, by using the C. neoformans-Galleria mellonella infection model, we demonstrated that DvAMP has significant therapeutic effects in vivo and that it significantly reduces the mortality and fungal burden of infected larvae. These results suggest that DvAMP may be a potential antifungal drug candidate for the treatment of cryptococcosis.