Assembly of Peptidoglycan Fragments-A Synthetic Challenge.

Fausto Queda,M Marques,Sérgio Filipe,Gonçalo Covas

doi:10.3390/ph13110392

Abstract

Peptidoglycan (PGN) is a major constituent of most bacterial cell walls that is recognized as a primary target of the innate immune system. The availability of pure PGN molecules has become key to different biological studies. This review aims to (1) provide an overview of PGN biosynthesis, focusing on the main biosynthetic intermediates; (2) focus on the challenges for chemical synthesis posed by the unique and complex structure of PGN; and (3) cover the synthetic routes of PGN fragments developed to date. The key difficulties in the synthesis of PGN molecules mainly involve stereoselective glycosylation involving NAG derivatives. The complex synthesis of the carbohydrate backbone commonly involves multistep sequences of chemical reactions to install the lactyl moiety at the O-3 position of NAG derivatives and to control enantioselective glycosylation. Recent advances are presented and synthetic routes are described according to the main strategy used: (i) based on the availability of starting materials such as glucosamine derivatives; (ii) based on a particular orthogonal synthesis; and (iii) based on the use of other natural biopolymers as raw materials.

Highlights

Peptidoglycan (PGN) is a major component of the cell wall that surrounds most bacteria
We described the different approaches developed to address the synthesis of the complex PGN structure from a scaffold of residues of NAG derivatives
PGN is a major constituent of the bacterial cell wall

Summary

Introduction

Peptidoglycan (PGN) is a major component of the cell wall that surrounds most bacteria It is a macromolecule made of glycan chains, which consist of linear alternating copolymers of β-1,4-linked N-acetyl glucosamine (GlcNAc or NAG) and N-acetyl muramic acid (MurNAc or NAM) residues. These glycan strands carry a lactyl group in the MurNAc moiety that is covalently bound to peptide stems via an amide bond. Modification of the bacterial process of PGN synthesis, or of PGN composition, can be associated with an altered expression of resistance to different antibiotics. After the incorporation of the PGN precursor into the PGN macromolecule, undecaprenyl pyrophosphate is subsequentially dephosphorylated, prior to its use in another cycle of glycan synthesis, leading to the removal of one phosphate group, and is recycled for another cycle of Lipid precursor synthesis [50,51]

Synthetic Approaches towards PGN Fragments from Glucosamine I

Findings

Conclusions