Improving Cell Selectivity of Fowlicidin‐1 by Swapping Residues between Pro‐7 and Tyr‐20

Abstract

Fowlicidin‐1 (Fowl‐1) is a cathelicidin antimicrobial peptide from chicken that has potent antimicrobial activity and considerable cytotoxicity for human erythrocytes and mammalian cells. To improve the selectivity for bacterial cells, a Fowl‐1 analog ([Y7,P20]‐Fowl‐1) was designed by swapping the amino acids between Pro‐7 and Tyr‐20 in Fowl‐1. [Y7,P20]‐Fowl‐1 maintained relatively good antimicrobial activity (MIC 4 to 8 μM) but was much less toxic to human erythrocytes and RAW 264.7 murine macrophage cells, as compared to Fowl‐1. Tryptophan fluorescence quenching suggested that the bacterial selectivity of [Y7, P20]‐Fowl‐1 is associated with a preferential interaction with anionic phospholipids. The three‐dimensional structure of the peptides predicted by the ITASSER server and reverse phase‐high performance liquid chromatography (RP‐HPLC) retention time revealed that the significant reduction in cytotoxicity of [Y7,P20]‐Fowl‐1 was correlated with increased structural flexibility and decreased hydrophobicity. The data increase the understanding of the antimicrobial activity of Fowl‐1 and the factors that influence bacterial selectivity.