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.

Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus (MRSA) through the replacement of l-allo-enduracididine with its isosteres

“…There has been very limited evaluation of teixobactin analogues against MRSA. Among the synthesised analogues, Orn10-teixobactin (3) (MIC 2 µg/mL) 5 and NorArg10-teixobactin 13 (MIC 16 µg/mL) 13 are the only ones tested against MRSA. However, a different strain of MRSA was used.…”

X-ray crystallographic structure of a teixobactin analogue reveals key interactions of the teixobactin pharmacophore

“…Two reports of the total synthesis of teixobactin have been published, 4,5 as well as a third describing the synthesis of the cyclic depsipeptide ring. 6 A 10-step synthesis of allo -enduracididine suitable for preparing gram-quantities has also been reported.…”

The impact of backbone N‐methylation on the structure‐activity relationship of Leu10‐teixobactin

“…There are two reported procedures that describe a convergent synthetic route to teixobactin analogues. One method utilises a serine ligation to prepare the native peptide from unprotected precursors via a 6+5 strategy . A second method also adopts this strategy but with protected fragments, although epimerisation of l ‐Ile 6 poses a risk during activation.…”