Fluorinated O-Phenylserine Residues Enhance the Broad-Spectrum Antimicrobial Activity of Ultrashort Cationic Lipopeptides

Abstract As a crucial structural element in many antimicrobial lipopeptides, phenylalanine poses a potential, but sensitive, point of modification in the pursuit of enhancing the antimicrobial efficacy of peptide antibiotics. We report the synthesis and application of a library of fluorinated O-phenyl serine analogues, followed by biological testing on relevant bacterial and fungal pathogens and the comparison of these analogues to commercial fluorinated phenylalanine amino acids. The synthetic aromatic residues were investigated for their enhanced potency over the original Phe when incorporated into a model ultrashort lipopeptide sequence derived from the octapeptin battacin and were found to enhance broad-spectrum antimicrobial activity across the panel of microbial species (while retaining non-hemolytic activity). While the major drawback of antimicrobial peptides is the cost of synthesis, they are some of the last antimicrobials to be majorly affected by antimicrobial resistance, making them a promising class of antibiotic for studying. Antimicrobial activity of the most potent fluorinated peptide was around 16-fold greater than the unfluorinated Phe-peptide against the fire blight pathogen, with milder increases in potency toward other pathogens such as S. aureus and E. coli. This indicates a potential future direction for these peptides to be developed as crop treatments to protect rosaceae from fire blight.