Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics

Yu Zong,Yu Rao,Kim Lewis,Kirsten J Meyer,Fang Fang,Liguo Wang,Hongying Gao,Zhihao Ni,Jingren Zhang

doi:10.1038/s41467-019-11211-y

Abstract

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block l-allo-Enduracidine in 30-gram scale in just one hour and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Staphylococcus aureus. We also propose that the antiparallel β-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking.

Highlights

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis
We attempted to accomplish the total synthesis of teixobactin in a convergent synthetic route in which we could readily change any amino acids to access teixobactin analogs without resorting to de novo synthesis in global solid-phase peptide synthesis (SPPS)
Drawing lessons from our previous procedure of yielding a series of teixobactin analogs by combining solution-phase with solid-phase synthesis, we proposed that teixobactin could be derived from a cyclic pentapeptide and a linear hexapeptide which could be constructed in solution-phase and solid-phase, respectively (“5 + 6”)[18]

Summary

Introduction

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Scalable synthesis of teixobactin has remained elusive, because of the tedious synthesis of L-allo-End and generation of diketopiperazine (DKP) by-product in SPPS8 (Fig. 1). Payne group constructed L-allo-End in seven steps from Boc-AspOtBu (compound 2)[8].

Results

Conclusion