Potent Analogues of Clovibactin from Commercially Available Amino Acid Building Blocks

High Resolution Image Download MS PowerPoint Slide This paper reports highly active analogues of clovibactin in which the rare, noncanonical 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 -Thr 5 -clovibactin. The resulting analogues ( d -Cha 2, d -Thr 5 -clovibactin, Cha 7, d -Thr 5 -clovibactin, and Cha 8, d -Thr 5 -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.