The Plant-Derived Peptide Hyde C1 Exhibits Membrane-Associated Antifungal Activity and Protects Against Systemic Candida albicans Infection

Atefeh Nikzad Alamshiri,1 Sima Sadat Seyedjavadi,2,* Fatemeh Peyravii Ghadikolaii,1,* Mehdi Goudarzi31Department of Biology, QaS.C., Islamic Azad University, Qaemshahr, Iran; 2Department of Mycology, Pasteur Institute of Iran, Tehran, Iran; 3Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran*These authors contributed equally to this workCorrespondence: Sima Sadat Seyedjavadi, Department of Mycology, Pasteur Institute of Iran, Tehran, 1316943551, Iran, Tel +98 21 64112804; +98 912 3826916, Email [email protected] Fatemeh Peyravii Ghadikolaii, Department of Biology, QaS.C., Azad University, Qaemshahr, Iran, Email [email protected]: Invasive candidiasis and increasing antifungal resistance underscore the need for alternative therapeutic approaches. Antimicrobial peptides are of interest because of their antifungal activity and potential membrane-associated effects. This study evaluated Hyde C1, a plant-derived antimicrobial peptide from Cichorium intybus, for antifungal activity against Candida albicans and examined whether its effects were associated with fungal membrane-associated effects.Methods: Antifungal activity against C. albicans ATCC 10231 was assessed using minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and time-kill assays. Membrane permeability and cellular morphology were examined by propidium iodide uptake, transmission electron microscopy, and scanning electron microscopy. Molecular docking assessed the predicted interaction of Hyde C1 with a model yeast membrane environment. Therapeutic effects were evaluated in a cyclophosphamide-induced murine model of systemic candidiasis by assessing survival, kidney fungal burden, and renal histopathology.Results: Hyde C1 showed antifungal activity with an MIC of 16 μg/mL and an MFC of 32 μg/mL. Time-kill analysis showed concentration- and time-dependent reductions in fungal viability. Hyde C1 increased propidium iodide uptake and produced ultrastructural and surface morphological alterations in fungal cells, findings consistent with membrane-associated antifungal activity. Docking analysis indicated a favorable predicted interaction with the model yeast membrane environment. In vivo, Hyde C1 treatment improved survival, reduced kidney fungal burden, and was associated with less pronounced infection-related renal histopathological changes than in untreated infected mice.Discussion: Hyde C1 exhibited antifungal activity against C. albicans and protective effects in a murine model of systemic candidiasis. The combined in vitro, computational, and in vivo findings support further investigation of this plant-derived peptide as an antifungal therapeutic candidate with membrane-associated activity. Additional studies are required to define its molecular mechanism, pharmacokinetic properties, safety profile, and reproducibility across broader experimental models.Keywords: Candida albicans, hyde C1, antifungal peptide, plant-derived antimicrobial peptide, systemic candidiasis, membrane-associated antifungal activity, murine model