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Antimicrobial peptides (AMPs) that selectively permeabilize bacterial membranes are promising alternatives to conventional antibiotics. Dimerization of AMP is considered an attractive strategy to enhance antimicrobial and membrane-lytic activity, but it also increases undesired hemolytic and cytotoxic activity. Here, we prepared Lys-linked homodimers of membrane-permeabilizing magainin II and cell-penetrating buforin II. Dimerization did not significantly alter conformational behavior, but it had a substantial impact on antimicrobial properties. We found that while the magainin II dimer showed increased antimicrobial and cytotoxic effects, the buforin II dimer conferred much greater antibacterial potency without exhibiting cytotoxic activity. Interestingly, the buforin II dimer was highly effective against several antibiotic-resistant bacterial isolates. Membrane permeabilization experiments indicated that the magainin II dimer rapidly disrupted both anionic and zwitterionic membranes, whereas the buforin II dimer selectively disrupted anionic membranes. Like the monomeric form, the buforin II dimer was efficiently translocated across lipid bilayers. Therefore, our results suggest that the dimerization of cell-penetrating buforin II not only disrupts the bacterial membrane, but also translocates it across the membrane to target intracellular components, resulting in effective antimicrobial activity. We propose that dimerization of intracellular targeting AMPs may present a superior strategy for therapeutic control of pathogenic bacteria.

Dimerization of cell-penetrating buforin II enhances antimicrobial properties