Modulation of Antimicrobial Activities of Aib‐Based Artificial Amphipathic α‐Helical Peptides by Incorporating Histidine Residues

Modulation of Antimicrobial Activities of Aib-Based Artificial Amphipathic α-Helical Peptides by Incorporating Histidine Residues

Regarding the acquisition of antibacterial activity of BKBA-20 derivatives against Gram-negative bacteria by histidine incorporation, the suitable introduction position depends on pH.

ABSTRACT

Cationic antimicrobial peptides (CAMPs) exhibit potent antibacterial activity by disrupting bacterial membranes. We investigated the effect of histidine incorporation on BKBA-20, a designed amphiphilic helical peptide composed of alternating 2-aminoisobutyric acid (Aib) and lysine. Substitution at lysine sites (1a1e series) reduced net charge and antimicrobial activity, though certain analogues (1c, 1d) demonstrated minimal antibacterial activity against Escherichia coli. In contrast, substitution at Aib sites (2a2c series) preserved some extent of helical structure and improved activity under acidic conditions. Notably, substitutions at the terminal of the peptide were more effective at acidic pH, while the slightly medial side of the peptide favored activity at neutral pH. Hemolysis assays confirmed low cytotoxicity of the modified peptides. These results suggest histidine incorporation as a promising strategy to broaden the spectrum of CAMPs, particularly against Gram-negative bacteria, without increasing toxicity.

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