Antibacterial peptide nanofibrils for targeted elimination of drug-resistant Staphylococci.
Antibacterial resistance represents a major global health challenge, particularly due to drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), which is known for causing persistent, biofilm-associated infections. In this study, we introduce self-assembling, tryptophan-rich peptide nanofibrils derived from DVFLGREEWWWWC (D4W) as potent antibacterial agents against Staphylococcus species, including MRSA. These self-assembling D4W units form amyloid fibril-like structures through controlled polarity reversal, enhancing their structural stability and antibacterial efficacy. The DVFLG motif enables selective recognition of Staphylococci, while the WWWW segment facilitates β-sheet formation and deep membrane penetration via hydrophobic interactions, effectively disrupting bacterial membranes. Moreover, D4W-derived nanofibrils engage in multivalent interactions with bacterial surfaces, significantly enhancing targeting precision and antibacterial efficacy. Beyond eradicating planktonic Staphylococci, D4W-derived nanofibrils significantly inhibit biofilm formation, a main factor in antibiotic resistance. Notably, D4W-derived nanofibrils exhibit low cytotoxicity and hemotoxicity, addressing their therapeutic potential. Their efficacy was validated in ex vivo pig skin and in vivo zebrafish embryo models, where they successfully inhibited MRSA growth. In addition, molecular dynamics simulations were employed to elucidate the interactions between D4W and model lipid membranes. This study introduces a strategy for designing effective antibacterial agents with enhanced stability, selectivity, and biofilm-prevention capabilities against drug-resistant Staphylococci. Our results indicate the promise of self-assembling peptide-based therapeutics in combating antibiotic-resistant Staphylococcal infections.