The discovery of antimicrobial peptides (AMPs) has brought tremendous promise and opportunities to overcome the prevalence of bacterial resistance to commonly used antibiotics. However, their widespread use and translation into clinical application is hampered by the moderate to severe hemolytic activity and cytotoxicity. Here, we presented and validated a supramolecular platform for the construction of hemo- and cytocompatible AMP-based nanomaterials, termed self-assembling antimicrobial nanofibers (SAANs). SAANs, the "nucleus" of our antimicrobial therapeutic platform, are supramolecular assemblies of de novo designed AMPs that undergo programmed self-assembly into nanostructured fibers to "punch holes" in the bacterial membrane, thus killing the bacterial pathogen. In this study, we performed solid-state NMR spectroscopy showing predominant antiparallel β-sheet assemblies rather than monomers to interact with liposomes. We investigated the mode of antimicrobial action of SAANs using transmission electron microscopy and provided compelling microscopic evidence that self-assembled nanofibers were physically in contact with bacterial cells causing local membrane deformation and rupture. While effectively killing bacteria, SAANs, owing to their nanoparticulate nature, were found to cross mammalian cell membranes harmlessly with greatly reduced membrane accumulation and possess exceptional cytocompatibility and hemocompatibility compared to natural AMPs. Through these systematic investigations, we expect to establish this new paradigm for the customized design of SAANs that will provide exquisite, tunable control of both bactericidal activity and cytocompatibility and can potentially overcome the drawbacks of traditional AMPs.
Keywords: antimicrobial nanomaterials; membrane interaction; peptides; self-assembly.