Synthesis and Structure-Activity Relationship Studies of N-Terminal Analogues of the Antimicrobial Peptide Tridecaptin A1

Chemical synthesis was used to increase the potency of the antimicrobial lipopeptide tridecaptin A(1). Lipid tail modification proved to be an ideal platform for synthesizing structurally simpler analogues that are not readily accessible by isolation. The stereochemical elements of the tridecaptin A(1) lipid tail are not essential for antimicrobial activity and could be replaced with hydrophobic aliphatic or aromatic groups. Some simpler analogues displayed potent antimicrobial activity against Gram-negative bacteria, including Campylobacter jejuni, Escherichia coli O157:H7, and multidrug resistant Klebsiella pneumoniae.