Peptide-based supramolecular assemblies represent an emerging and important class of biomaterials that have been extensively utilized in various biomedical fields, including drug delivery, vaccination and 3-D cellular scaffolds. Surprisingly, such peptide assemblies have rarely been directed toward antimicrobial therapy development which has been considered as an urgent biomedical problem to tackle along with cancer therapy and tissue regeneration. In this work, we present the first example of de novo designed multidomain peptides (MDPs) that form self-assembling antimicrobial nanofibers (SAANs) with a broad-spectrum antimicrobial activity. SAANs, the ‘nucleus’ of our antimicrobial therapeutic platform, are supramolecular assemblies of de novo designed β-sheet-forming MDPs with a general formula of Kx(QL)yKz. Unlike most AMPs that exist as a monomer prior to their binding with lipid membranes, MDPs can be formulated into supramolecular nanofibers through proper balance of the number of lysine residues and repeating units of the (QL) domain. The formation of SAANs offers a huge advantage over previously designed monomeric AMPs in that the assembled nanofibers exhibit enhanced cell penetration and protects individual peptides against proteolysis while dramatically reducing their toxic and reactogenic effects on eukaryotic cells. To our knowledge, this is a unique set of properties, which has yet to be evaluated for its antimicrobial potential. This study details a design strategy to optimize supramolecular AMPs for minimal cytotoxicity, enhanced proteolytic stability, potent cell penetration and effective antimicrobial activity, thereby facilitating their application for systemic anti-infective treatments.

Self-assembling antimicrobial nanofibers based on supramolecular peptide assemblies

249th National Meeting (2015)

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