Fowlicidin‐3 Analog with Improved Cell Selectivity Synthesized by Shifting a PXXP Motif from the N‐Terminus to a Central Position.

Fowlicidin‐3 (Fow‐3), a chicken‐derived cathelicidin, is an antimicrobial peptide with considerable antimicrobial activity and mammalian cell toxicity. To reduce toxicity toward mammalian cells and improve selectivity for bacteria, a Fow‐3 analog was synthesized by shifting its PXXP motif from the N‐terminus to a central position. This analog was more selective against bacteria and was less toxic to mammalian cells, including human erythrocytes, than Fow‐3. Circular dichroism and retention time in reversed‐phase high‐performance chromatography demonstrated that the drastic decrease in mammalian cell toxicity of the Fow‐3 analog correlated with increased conformational flexibility and decreased hydrophobicity. This analog had potent antimicrobial activity against antibiotic‐resistant bacteria, including methicillin‐resistant Staphylococcus aureus, multidrug‐resistant <italic>Pseudomonas aeruginosa</italic>, and vancomycin‐resistant <italic>Enterococcus faecium</italic>. Furthermore, this analog was more synergistic with chloramphenicol and oxacillin compared to LL‐37, against a multidrug‐resistant strain of <italic>P. aeruginosa</italic>. Thus, repositioning the proline residues to the center of the α‐helical antimicrobial peptides improved cell selectivity. [ABSTRACT FROM AUTHOR]