and Antifungal Efficacy and Safety of the Def2.1 Peptide against the Neglected and Drug-Resistant Pathogen.

The growing threat of fungal infections, driven by increasing drug resistance, has become a major global health concern. Candidiasis, a common human infection, is associated with high mortality, particularly in invasive cases. Among non- (NAC) species, (renamed ) is of clinical importance because of its intrinsic resistance to fluconazole, complicating treatment options. This study evaluated the antifungal efficacy and safety of the bioinspired peptide Def2.1 (CDF-GK) against NAC species, with a specific focus on , through a series of and tests. CDF-GK effectively inhibited the growth of several yeast species, including , , , and , with MIC values ranging from 3.12 to 200 μM. The peptide demonstrated particularly strong activity against , with an MIC of 25 μM, an MFC of 50 μM, and an IC of 5 μM, surpassing the effectiveness of fluconazole. Additionally, CDF-GK inhibited biofilm formation, caused 100% cell death within 1 h, permeabilized the cell membrane, interacted with ergosterol, induced oxidative stress, mitochondrial dysfunction, and vacuolar fragmentation, and entered the intracellular space of . assays using larvae confirmed the low toxicity of CDF-GK, even at high concentrations, and significantly improved the survival of infected larvae with minimal activation of cellular and humoral immune responses. These findings indicate that CDF-GK holds great promise as a therapeutic agent for infections, as it combines potent antifungal action with safety in both and models.