The depsi-peptide teixobactin exhibits potent antimicrobial activity against several Gram-positive bacterial strains and without the development of any detectable resistance [1,2]. It therefore has enormous therapeutic potential as an anti-infective agent, which could help address the problem of antimicrobial resistance. The development of rapid synthetic routes for preparing teixobactin analogues is essential to enable the identification of new variants with improved pharmacological properties. In this study, we report a convergent synthetic approach via assembly of the C-terminal tetrapeptide macrocycle in excellent yield, followed by a racemisation-free solution-phase ligation with the N-terminal heptapeptide. An N-methyl scan of the N-terminal segment was also conducted [3], which provides further insights into teixobactin’s structure-activity relationships. These findings will help inform the design of novel teixobactin analogues with greater potency and a broader spectrum of activity.
[1] Ling, L. L. et al., Nature, 2015, 517, 455-459.
[2] Karas, J. A. et al., Ann. N. Y. Acad. Sci., 2020, 1459, 1, 86-105.
[3] Velkov, T. et al., J. Pept. Sci., 2019, 25, 9, e3206.