Biogenesis and Function of Streptococcus Pyogenes Cell Wall

The group A streptococcus (GAS, Streptococcus pyogenes) is a leading bacterial pathogen of the human pharynx and skin. In recent years, a striking resurgence in severe invasive GAS infections has been observed worldwide. GAS infections account for more than 650,000 cases of severe invasive disease annually. The invasive GAS infections, necrotizing fasciitis, cellulitis and erysipelas with concomitant scarlet fever and streptococcal toxic syndrome, are difficult to treat with antibiotics, and GAS vaccine is urgently needed to combat this neglected disease. A major component of the GAS cell wall is the Group A Carbohydrate (GAC) covalently linked to peptidoglycan, consisting of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc) side-chains. GAC is an attractive vaccine candidate due to its conserved expression in all GAS serotypes and the absence of its constitutive component, rhamnose, in humans. Our genetic, biochemical and structural studies identified two novel modifications of GAC glycans: glycerol phosphate modification of the GlcNAc side-chains and N-deacetylation of the linkage unit which joins GAC to peptidoglycan. The goal of this proposal is to re-examine GAC structure and characterize the mechanism of GAC modifications and their biological functions. To help answer these important biological questions we will use a range of genetic, biochemical, analytical and structural approaches. The function of GAC modifications in GAS pathogenesis will be studied in a mouse models of infection. The proposed studies provide a platform for design of a safe and effective vaccine against this important human pathogen. Since the enzymes of GAC biosynthesis pathway are attractive drug targets, the proposed studies will have implications for drug design.