Re-evaluation of the N-terminal substitution and the D-residues of teixobactin

Abstract

Teixobactin is a head to side-chain cyclic depsipeptide with a guanidino based residue within the cycle, three D-amino acids in the tail, and a N-methylated terminal residue. The synthesis of the first analogue, containing Arg, was recently described by our group. Herein, we demonstrated that analogues of Arg. Teixobactin bearing either (a) three L-amino acids in the tail and keeping the N-methyl at the N-terminal or (b) with three D-amino acids, but with acetylation of the N-terminal, are inactive against Gram(+) and Gram(−) bacteria. These results complement those published by the groups of Madder, Taylor, and Singh that have shown that both modifications: L-amino acids and N-acetylation also led to loss of biological activity.