We report a dimerization strategy to enhance the antibacterial potency of an otherwise weak cationic amphiphilic polyproline helical (CAPH) peptide. Overall, the dimeric CAPHs were more active against Escherichia coli and Staphylococcus aureus than the monomeric counterpart, reaching up to a 60-fold increase in potency. At their minimum inhibitory concentration (MIC), the dimeric peptides demonstrated no hemolytic activity or bacterial membrane disruption as monitored by β-galactosidase release in E. coli. At higher concentrations the dimeric agents were found to induce β-galactosidase release, but maintained negligible hemolytic activity, pointing to a potential shift in the mechanism of action at higher concentrations. Thus, discontinuous dimerization of an unnatural proline-rich peptide was a successful strategy to create potent de novo antibacterial peptides without membrane lysis.
Keywords: Antimicrobial peptide; Dimerization; Non-lytic; Proline-rich.
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