Synthesis and biological studies of ribitol phosphate oligomers in S. aureus wall teichoic acid

Abstract

Staphylococcus aureus is a gram-positive bacterium that is a major cause of infections in communities and hospitals, including pneumonia, bacteremia, endocarditis, and wound infection. In particular, methicillin-resistant Staphylococcus aureus (MRSA) is a strain resistant to the beta-lactam antibiotics, and it is difficult to treat and poses a great threat to public health worldwide. Many approaches and strategies have been tried around the world to develop a novel vaccine against MRSA, but, until now, effective vaccines have not been developed. Therefore, a new vaccine target candidate against MRSA infection is urgently needed.

Wall Teichoic Acid (WTA) is an electrically negative sugar molecule present in gram-positive bacterial cell walls such as Staphylococcus aureus. It is known that WTA is related to the concentration control of metal ions between the inside and the outside of the cell and settlement of cell wall and expansion of bacterial colonies. In the past few years, some independent research groups showed that WTA plays an important role in the immune response, and the possibility of developing a new drug or vaccine using WTA has emerged. However, systematic immune studies using WTA isolated from Staphylococcus aureus are difficult because of the molecular struc-tural diversity of the molecules themselves and the incomplete purification.

In this thesis, ribitol phosphate (Rbo P), a major component of WTA, is synthesized through organic synthesis and its biological activity is discussed. A suitable building block was designed to synthesize the ribitol phosphate moiety and a building block could be synthesized from the pentose D-ribose and its derivatives which can be easily obtained in the nature. The building blocks were oligomerized through phosphoramidite chemistry, which is often used for DNA synthesis. After last global deprotection step, we could obtain a series of ribitol phosphate oligomers and the synthesized oligomers showed biological activities in vivo animal experiments using mice. These results are expected to be used as a basic study for vaccine and drug development of methicillin-resistant Staphylococcus aureus in the future.