Structure–Activity Relationship in ε-Lysine Peptides: The Length Effects on Antifungal Activity

Polymers with multiple ε-lysine residues exhibit excellent antibacterial activity and membrane selectivity for bacteria and fungi. This study investigated the optimal number of ε-lysine residues required for antimicrobial activity by comparing peptides with 12, 14, 16, and 18 ε-lysine residues to ε-poly-l-lysine (εPL). Peptides with 16-18 ε-lysine residues showed submicromolar minimum inhibitory concentrations (MICs) against Gram-positive and Gram-negative bacteria while higher MICs for antifungal activity. εPL demonstrated rapid fungicidal activity by disrupting fungal membranes, inhibiting hyphal growth, and eradicating biofilms in vitro. In rabbit models of corneal epithelial injury, εPL did not impede wound healing. Topical or intrastromal εPL significantly reduced fungal burden and disease severity in a rabbit model of <i>Fusarium</i> keratitis. In a mouse model of <i>Candida</i> keratitis, εPL significantly decreased anterior chamber inflammation and fungal burden compared to voriconazole. These promising findings highlight the potential of εPL as an antifungal agent for the management of fungal keratitis.