Chemical synthesis of the artificial wall teichoic acid derivatives in Staphylococcus aureus

Abstract

Staphylococcus aureus induces diverse diseases such as skin infections, bacteremia, and sepsis, being recognized as significant causes of morbidity and mortality in the clinic. The common treatment for S. aureus is $\beta$-lactam antibiotics. However, antibiotic-resistant strains, such as Methicillin-resistant Staphylococcus aureus (MRSA), emerged throughout the world. For this reason, a new vaccine against MRSA infection is urgently needed. Recently, wall teichoic acid (WTA), which is a major membrane-attached glycopolymer of S. aureus, has been shown to play a crucial role in human innate immunity. It induces human mannose binding lectin and $\gamma \delta$ T cell, leading to bacterial clearance during re-infection. Also, extracted WTA from natural bacteria is hard to identify the exact structural information of each component and has low antigenicity. Thus, the synthesis of S. aureus WTA and derivatives is much necessary. S. aureus WTA consists of ribitol-phosphate (RboP) repeating units and two glycerol-phosphates (GroP) attached to saccharides. Cationic D-alanine and N-acetylglucosamine are presumed to bind to the hydroxyls on the RboP repeating units. The synthetic studies of GroP oligomers have been studied but more complicated RboP oligomers have not yet been reported. Inspired by the solid-phase oligonucleotide synthesis, RboP monomers are prepared from D(-)-ribose and each monomer contains different combination of two residues. D-alanine residue is attached to ribitol backbone via the Schotten-Baumann reaction or a coupling reagent, DEPBT, to reduce the epimerization. Another residue, N-acetylglucosamine, is also attached to ribitol backbone via $\beta$-selective glycosylation. Furthermore, RboP oligomers are directly synthesized by the solution-phase synthesis using phosphoramidite chemistry.