Abstract
Precise control over peptide nanonet architecture is instrumental in advancing the development of antibacterial nanonets. Here, a novel design strategy is presented to control bacteria nanonet morphology through rational modification of the β-hairpin side strands, leveraging the unique chemical properties of amino acid side chains. By fine-tuning both the termini and aromaticity of the hydrophobic residue, the W-W(13) peptide is engineered to form increased nanofibers interweaving on bacterial surfaces, forming a tightly interwoven nanonet that effectively traps and kills both E. coli and S. aureus. In contrast, asymmetric glutamic acid substitutions on the cationic residues of the E-E(13) (ASYM) peptide redirect the nanofibers to self-interweave, forming extensive nanonets with minimal bacterial coverage and no antibacterial activity. Using these nanonets with distinct morphologies and function, it is demonstrated that the formation of tightly interwoven nanonets on bacterial surfaces significantly reduces the spread of motile E. coli and P. aeruginosa, outperforming both loosely trapping nanonets and conventional potent antibiotics. The findings pave the way for the development of novel peptide-based nanonets, offering a promising strategy to target bacterial motility and prevent spreading of bacteria.