Combating Antibiotic-Resistant Bacterial Infection Using Coassembled Dimeric Antimicrobial Peptide-Based Nanofibers

The emergence of multidrug-resistant (MDR) pathogens, coupled with the limited effectiveness of existing antibiotics in eradicating biofilms, presents a significant threat to global health care. This critical situation underscores the urgent need for the discovery and development of antimicrobial agents. Recently, peptide-derived antimicrobial nanomaterials have shown promise in combating such infections. Amino acid noncovalent forces, notably π-π stacking and electrostatic interactions, remain underutilized for guiding the coassembly of peptides into bacteriostatic nanomaterials. Thus, we constructed a dimeric nanopeptide system using the disulfide bonds of cysteine. The self-assembly of dimeric peptides into nanofibers was realized by the interaction of π-π aromatic amino acids (Trp, Phe, and Pyr) and the electrostatic attraction between oppositely charged amino acids (Asp and Arg). The optimal dimeric peptide 2D2W exhibits potent antibacterial activity against resistant bacteria and is nontoxic. Mechanistically, 2D2W penetrated the outer membrane after electrostatic adsorption, resulting in plasma membrane depolarization, homeostatic disruption, and ultimately bacterial death. In a mouse model of peritonitis, 2D2W demonstrated efficacy in the in vivo treatment of bacterial infections. In conclusion, the design of dimeric nanopeptides co-driven by intermolecular forces provides a promising avenue for the development of high-performance antimicrobial nanomaterials. These advances may also facilitate the application and advancement of peptide-based bacteriostatic agents in clinical practice.