Abstract
The unusual d-l-l-d-d-l-l pattern of stereochemistry in residues 1-7 of the peptide antibiotic teixobactin is critical to its extraordinary antibiotic activity, creating an unusual amphiphilic β-sheetlike structure that is essential to its mechanism of action. The current study sought to replace the three d-amino acids in the tail with l-amino acids while maintaining amphiphilicity. We find that swapping residues d-Gln4 and d-allo-Ile5 in O-acyl isopeptide prodrugs of teixobactin permits the introduction of l-stereochemistry with retention of antibiotic activity. Nevertheless, modifying the N-terminal stereochemistry results in a loss of antibiotic activity.