Total synthesis of teixobactin

Abstract

To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product.

Figure 1. The structures of some cyclic peptide-based lipid II inhibitors.

(a) Enduracidins A and B were discovered in late 1960s by Nakazawa and Mizuno et al. The structure of Ramoplanin was established in 1989 by Cavalleri et al. Mannopeptimycin was isolated in 1950s and first elucidated around 2002 (ref. 17). (b) Teixobactin was discovered in 2015 as a new lipid II inhibitor. Our synthetic disconnection of teixobactin was also described.

Figure 2. Synthetic route towards teixobactin.

Peptides 9 and 11 were prepared by SPPS and coupled through Ser ligation, which was developed in our group.

Figure 3. HPLC spectra of peptide cyclizations.

(a) Purified cyclic peptide with D-Thr. (b) Crude cyclization mixture of the one with L-allo-Thr. (c) Co-elution of a and b.