EXPLORING THE SYNERGISTIC INTERACTION OF POLYBIA-DERIVED ANTIMICROBIAL PEPTIDES WITH MODEL FUNGAL MEMBRANES.

The growing resistance of fungi to traditional antifungal drugs, coupled with their associated toxicity, has driven the search for novel therapeutic strategies that are both more effective and less harmful. In this context, antimicrobial peptides (AMPs) have emerged as promising alternatives due to their low molecular weight, broad-spectrum activity, and reduced potential to induce resistance. Among these, Polybia-MPI (MP1) and Polybia-MPII (MP2)—peptides derived from the venom of the social wasp Polybia paulista —have shown significant antimicrobial properties. MP2 exhibits potent activity against bacteria and fungi but is limited by its high hemolytic activity. Conversely, MP1 displays antibacterial and anticancer activity with low cytotoxicity. Notably, both peptides have shown potential in inhibiting biofilm formation, a critical factor in persistent infections. The electrostatic interaction between AMPs and anionic membranes is fundamental to their selectivity and efficacy. The amino acid composition and spatial distribution of acidic and basic residues in MP1 and MP2 influence their net charge and, consequently, their binding affinity to fungal membranes. These effects are modulated by environmental pH and membrane potential, as described by the Gouy–Chapman theory. Preliminary studies suggest that combining MP1 and MP2 may enhance antimicrobial efficacy while reducing cytotoxicity, as observed in the inhibition of Staphylococcus aureus biofilms. This project aims to investigate the synergistic interaction of MP1 and MP2 in fungal model membranes containing phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and ergosterol (Erg), as well as eukaryotic-like membranes with PC and cholesterol. A multidisciplinary experimental approach will be employed. Circular dichroism (CD) spectroscopy will assess peptide-induced structural changes. Zeta potential measurements will evaluate electrostatic interactions, and fluorescence assays will determine peptide binding constants. Additionally, membrane disruption and morphological effects will be explored using giant unilamellar vesicles (GUVs). This study will provide fundamental insights into the physicochemical mechanisms underlying AMP-membrane interactions and inform the design of effective antifungal therapies based on synergistic peptide combinations.