"Novel points of attack" – Exploiting capsule biosynthesis in Streptococcus pneumoniae for antibacterial treatment

The polysaccharide capsule is the major virulence factor of pneumococci and crucial to resist the immune system during an infection. Whereas vaccines that target pneumococcal capsules are in use for decades, neither biosynthetic reactions nor mechanisms regulating capsule expression have been investigated as potential therapeutic targets so far. Most S. pneumoniae serotypes produce capsular polysaccharides (CP) via the Wzx/Wzy-dependent pathway. In this case, CP repeat units are assembled on C₅₅-P at the inner side of the cytoplasmic membrane, translocated and polymerized in a non-processive manner on the exterior of the cell. Enzymes of the LytR-CpsA-Psr (LCP) family catalyze the transfer and the covalent linkage of CP to peptidoglycan (PGN) under release of the lipid carrier. Here we show the functional reconstitution of the CP biosynthesis reactions of S. pneumoniae ST14 in vitro using purified recombinant enzymes and substrates. In addition, we provide first biochemical evidence and molecular details for the post-translational regulation of involved reactions, which allows the concerted action of CP and PGN biosynthesis reactions.