Self-Assembled Peptide Nanofibers Display Natural Antimicrobial Peptides to Selectively Kill Bacteria without Compromising Cytocompatibility

One of the major hurdles in the development of antimicrobial peptide (AMP)-based materials is their poor capacity in selectively killing bacteria without harming nearby mammalian cells. Namely, they are antimicrobial but cytotoxic. Current methods of nanoparticle-encapsulated AMPs to target bacteria selectively still have not yet overcome this hurdle. Here, we demonstrate a simple yet effective method to address this daunting challenge by associating a natural AMP with a β-sheet-forming synthetic peptide. The integrated peptides self-assembled to form a supramolecular nanofiber, resulting in the presentation of the AMP at the nanofiber-solvent interface in a precisely controlled manner. Using melittin as a model natural AMP, we found that the conformation of melittin changed dramatically when presented on the nanofiber surface, which, in turn, modulated the induced membrane permeability of the bacterial and mammalian cell membranes. Specifically, the presentation of melittin on the nanofiber restricted its hydrophobic residues, leading to a reduction of the hydrophobic interaction with lipids in the cell membranes. Compellingly, the reduced hydrophobic interaction led to a considerable decrease of melittin's induced permeability of the mammalian cell membrane than that of the bacterial cell membrane. As a result, the AMP-displaying nanofiber preferentially permeabilized and disrupted the membrane of the bacteria without compromising the mammalian cells. Such improved membrane selectivity and cytocompatibility were confirmed in a cell-based membrane localization and live-dead assay. Our new strategy holds great promise for fabricating cytocompatible antimicrobial assemblies that offer safer and more effective administration of therapeutic AMPs. These assemblies, with intrinsic antimicrobial activity and cytocompatibility, can also serve as building blocks for the construction of higher-ordered scaffolds for other biomedical applications such as tissue engineering and regenerative medicine.