Programmable Peptide Nanofibers Enable Effective MRSA Biofilm Eradication and Infection Control

With antibiotic-resistant bacterial strains rapidly increasing and the development of antibacterial drugs stagnating, alternative solutions are urgently needed. Antimicrobial peptides (AMPs) have emerged as promising therapeutics due to their structural diversity and broad-spectrum activity against pathogens. This versatility is particularly attractive for combating drug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA), which is notorious for causing persistent and biofilm-related infections. In this study, we engineered a series of tryptophan-arginine-rich antimicrobial peptides, i.e., DVFLGREEWWWWWWC (D6W), DVFLGREEWWWRWWWC (D6W1R), and DVFLGREEWWRWWRWWC (D6W2R), specifically targeting S. aureus. The DVFLG domain confers selective affinity toward S. aureus, while tryptophan- and arginine-rich segments promote bacterial membrane disruption. Structural analysis reveals that these peptides adopt a mixture of α-helix or β-sheet conformations and spontaneously self-assemble into fibrillar or oligomeric supramolecular structures. Among the three peptides tested, D6W2R exhibited the highest antibacterial activity, consistent with trends observed in the molecular dynamics simulations. Beyond eradicating planktonic bacteria, the resulting peptide nanofibers effectively inhibit biofilm formation and disrupt established biofilms. Notably, their antibacterial performance is preserved under ex vivo and in vivo conditions while exhibiting minimal toxicity toward mammalian cells. These results demonstrated that self-assembled peptides can encode potent, selective antibacterial activity against MRSA, especially against biofilm-related infections.