Designed peptide nanopores enable programmable antimicrobial action against drug‑resistant bacteria
A computationally driven framework designs ~30‑residue α‑helical peptides that self‑assemble into stable barrel‑stave transmembrane nanopores, with design rules based on aromatic stacking, salt bridges and charged termini validated by MD simulations and experiments. Lead peptides KDFA2i + 9‑NH2 and KDFC16 + 9‑NH2 show submicromolar activity against drug‑resistant ESKAPEE pathogens, strong selectivity with low human toxicity, and inner‑membrane depolarization via pore formation confirmed by calcein leakage, electrophysiology and AFM. KDFA2i + 9‑NH2 demonstrates in vivo anti‑infective efficacy in mouse skin abscess and thigh infection models and good serum stability. AlphaFold predictions could not reliably reproduce barrel‑stave pores, highlighting the need for membrane‑explicit simulations. Overall, the study establishes a general, programmable nanopore design platform with potential biomedical and biotechnological applications.
