Elucidation of the Teixobactin Pharmacophore

This paper elucidates the teixobactin pharmacophore by comparing the arginine analogue of teixobactin Arg₁₀-teixobactin to seven homologues with varying structure and stereochemistry. The roles of the guanidinium group at position 10, the stereochemistry of the macrolactone ring, and the “tail” comprising residues 1–5 are investigated. The guanidinium group is not necessary for activity; Lys₁₀-teixobactin is more active than Arg₁₀-teixobactin against Gram-positive bacteria in minimum inhibitory concentration (MIC) assays. The relative stereochemistry of the macrolactone ring is important. Diastereomer l-Thr₈,Arg₁₀-teixobactin is inactive, and diastereomer d-<i>allo</i>-Ile₁₁,Arg₁₀-teixobactin is less active. The macrolactone ring is critical; <i>seco</i>-Arg₁₀-teixobactin is inactive. The absolute stereochemistry is not important; the enantiomer <i>ent</i>-Arg₁₀-teixobactin is comparable in activity. The hydrophobic <i>N</i>-terminal tail is important. Truncation of residues 1–5 results in loss of activity, and replacement of residues 1–5 with a dodecanoyl group partially restores activity. These findings pave the way for developing simpler homologues of teixobactin with enhanced pharmacological properties