Abstract
The cell wall of the human bacterial pathogen Group A Streptococcus (GAS) consists of peptidoglycan decorated with the Lancefield group A carbohydrate (GAC). GAC is a promising target for the development of GAS vaccines. In this study, employing chemical, compositional, and NMR methods, we show that GAC is attached to peptidoglycan via glucosamine 1-phosphate. This structural feature makes the GAC-peptidoglycan linkage highly sensitive to cleavage by nitrous acid and resistant to mild acid conditions. Using this characteristic of the GAS cell wall, we identify PplD as a protein required for deacetylation of linkage N-acetylglucosamine (GlcNAc). X-ray structural analysis indicates that PplD performs catalysis via a modified acid/base mechanism. Genetic surveys in silico together with functional analysis indicate that PplD homologs deacetylate the polysaccharide linkage in many streptococcal species. We further demonstrate that introduction of positive charges to the cell wall by GlcNAc deacetylation protects GAS against host cationic antimicrobial proteins.
Highlights
The cell wall of the human bacterial pathogen Group A Streptococcus (GAS) consists of peptidoglycan decorated with the Lancefield group A carbohydrate (GAC)
This hypothesis is based on the observation that the biosynthetic pathways of GAC, and the S. aureus and B. cereus wall teichoic acids (WTAs) share initiating steps catalyzed by GacO homologs, providing the first sugar residue GlcNAc for the polysaccharide biosynthesis (Supplementary Fig. 1)[2,8,13,17]
Glycoconjugate vaccines obtained by covalent linkage of bacterial polysaccharides to carrier proteins have been proven highly successful in the prevention of a number of infectious diseases[54]
Summary
The cell wall of the human bacterial pathogen Group A Streptococcus (GAS) consists of peptidoglycan decorated with the Lancefield group A carbohydrate (GAC). In this study, employing chemical, compositional, and NMR methods, we show that GAC is attached to peptidoglycan via glucosamine 1-phosphate This structural feature makes the GAC-peptidoglycan linkage highly sensitive to cleavage by nitrous acid and resistant to mild acid conditions. Using this characteristic of the GAS cell wall, we identify PplD as a protein required for deacetylation of linkage N-acetylglucosamine (GlcNAc). The LytRCpsA-Psr (LCP) phosphotransferases transfer GAC from the lipid carrier to peptidoglycan (Fig. 1a) This proposed assembly mechanism is consistent with other isoprenol-mediated polysaccharide biosynthetic pathways in Gram-positive bacteria. We reveal that deacetylation of the cell wall GlcNAc residues protects GAS from host small cationic antimicrobial proteins (AMPs)
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