Potent Analogues of Clovibactin from Commercially Available Amino Acid Building Blocks

This paper reports highly active analogues of clovibactin in which the rare, non-canonical amino acid D-hydroxyasparagine is replaced with the commercially available amino acid D-threonine. Sequential mutation of leucines 2, 7, and 8 to the more hydrophobic homologue cyclohexylalanine dramatically increases the antibiotic activity of D-Thr5-clovibactin. The resulting analogues (D-Cha2,D-Thr5-clovibactin, Cha7,D-Thr5-clovibactin, and Cha8,D-Thr5-clovibactin) are readily prepared by standard peptide synthesis techniques and exhibit excellent activity (≤ 1 μg/mL) against the Gram-positive, drug-resistant pathogens MRSA and VRE.