ABSTRACTThe emergence of azole-resistant and biofilm-formingCandidaspp. contributes to the constantly increasing incidence of vulvovaginal candidiasis. It is imperative to explore new antifungal drugs or potential substituents, such as antimicrobial peptides, to alleviate the serious crisis caused by resistant fungi. In this study, a novel antimicrobial peptide named Scyampcin44–63was identified in the mud crabScylla paramamosain. Scyampcin44–63exhibited broad-spectrum antimicrobial activity against bacteria and fungi, was particularly effective against planktonic and biofilm cells ofCandida albicans, and exhibited no cytotoxicity to mammalian cells (HaCaT and RAW264.7) or mouse erythrocytes. Transcriptomic analysis revealed four potential candidacidal modes of Scyampcin44–63, including promotion of apoptosis and autophagy and inhibition of ergosterol biosynthesis and the cell cycle. Further study showed that Scyampcin44–63caused damage to the plasma membrane and induced apoptosis and cell cycle arrest at G2/M inC. albicans. Scanning and transmission electron microscopy demonstrated that Scyampcin44–63-treatedC. albicanscells were deformed with vacuolar expansion and destruction of organelles. In addition,C. albicanscells pretreated with the autophagy inhibitor 3-methyladenine significantly delayed the candidacidal effect of Scyampcin44–63, suggesting that Scyampcin44–63might contribute to autophagic cell death. In a murine model of vulvovaginal candidiasis, the fungal burden of vaginal lavage was significantly decreased after treatment with Scyampcin44–63.