Synthetic Antimicrobial Peptides: IV. Effect of Cationic Groups of Lysine, Arginine, and Histidine on Antimicrobial Activity of Peptides with a ‘Circular’ Type of Amphipathicity

The antimicrobial and hemolytic activities of synthetic antimicrobial peptides (SAMP) XFXXFFXXFF (X5F5) with a 'circular' (helical or cyclic) type of amphipathicity (CTA) has been studied. The studied peptides contain cationic amino acid residues of arginine, lysine, or histidine (X = Arg, Lys, or His). These peptides have been shown to exhibit more than eight times higher antibacterial and ~2 times lower antifungal activity as compared with SAMP XXXXXXXXXFF (X9F2) with a 'linear' type of amphipathicity (LTA). It has been found that the peptides that contain the cationic arginine residues have the highest antibacterial activity, and the histidine-containing peptides have the lowest antibacterial activity. On the contrary, the histidine-containing peptides have the highest fungicidal activity against fungal cultures of Candida albicans. The X5F5 peptides, regardless of their cationic composition, exhibit increased hemolytic activity (20–60% hemolysis at 500-µM peptide concentration in the medium) compared to the X9F2 peptides with a linear type of amphipathicity (no more than 4% hemolysis at the same peptide concentrations). Despite their relatively high hemolytic activity, the average bacterial selectivity of the X5F5 peptides remains quite high; their average geometric therapeutic index (AG TI) is ~10, except for histidine-containing peptides H5F5 (AG TI = 0.5). At the same time, the selectivity of the histidine-containing peptide H5F5 to fungal cells (TI = 2.7) is five times higher than that to bacterial cells but 200 times lower than the fungicidal selectivity of the histidine-containing peptide H9F2 with a 'linear' amphipathic type (TI = 571.4). The arginine- and lysine-containing peptides with a circular type of amphipathicity (R5F5 and K5F5) and histidine-containing peptides with a linear type of amphipathicity (Н9F2) can be recommended to create antibacterial and antifungal drugs, respectively.