Teixobactin “Swapmers”\nwith l Tail Stereochemistry Retain Antibiotic Activity

The unusual d-l-l-d-d-l-l pattern of stereochemistry in residues\n1–7\nof the peptide antibiotic teixobactin is critical to its extraordinary\nantibiotic activity, creating an unusual amphiphilic β-sheetlike\nstructure that is essential to its mechanism of action. The current\nstudy sought to replace the three d-amino acids in the tail\nwith l-amino acids while maintaining amphiphilicity. We find\nthat swapping residues d-Gln<sub>4</sub> and d-<i>allo</i>-Ile<sub>5</sub> in <i>O</i>-acyl isopeptide\nprodrugs of teixobactin permits the introduction of l-stereochemistry\nwith retention of antibiotic activity. Nevertheless, modifying the <i>N</i>-terminal stereochemistry results in a loss of antibiotic\nactivity.