Peptide G3 Suppresses Hyphal Development in Candida albicans by Disrupting β-1,3-Glucan

Abstract The increasing incidence of invasive candidiasis, driven by the hyphal morphology and virulence of Candida albicans (C. albicans), underscores an urgent need for alternative strategies to attack the fungus. In this study, we describe the potent fungistatic activity of the short peptide G3, which specifically suppresses hyphal development of C. albicans by targeting β-1,3-glucan on the fungal cell wall. Under hypha-inducing conditions, G3 inhibits yeast-to-hypha transition in a concentration- and time-dependent manner, achieving complete suppression at 30 μM. Mechanistic investigations reveal that G3 selectively binds to the surface-exposed β-1,3-glucan, triggering a conformational transition from random coil to amphipathic helix. This binding leads to the formation of surface granules that increase cell wall roughness. Further biophysical and biochemical analyses reveal that G3 induces measurable remodeling of the cell wall, including a decrease in the β-1,3-glucan signal detectable with Congo red (48.2%, normalized to biomass). As a result, the growth and hyphal transformation of C. albicans are completely suppressed, and such a mechanism offers a strategic approach to combat invasive fungal infections with a reduced risk of resistance development.