The Gram-negative bacteria (GNB) Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are the etiologic agents of melioidosis and glanders, respectively, and are endemic in tropical and subtropical regions. Due, among others, to their high mortality rate, their possible inoculation by inhalation, their intrinsic resistance to commonly used antibiotics, and the actual lack of vaccines against these diseases, the Centers for Disease Control and Prevention have classified Bp and Bm as potential bioterrorist weapons . Owing to the dangers that Bp and Bm pose for the society, our project aims to prevent melioidosis and glanders infections by developing synthetic glycoconjugate vaccines against these pathogens.
Diverse polysaccharides are anchored in the outer membrane of GNB cells, including lipopolysaccharides (LPS). The O-antigen (OAg) portion of the LPS constitutes one of the main virulence determinant and protective antigen of Bp and Bm . It consists of a linear heteropolymer whose repeating unit is a disaccharide composed of glucose and diversely acetylated/methylated 6-deoxy-talose moieties. Our team has recently reported the antigenic and immunogenic potential of synthetic oligosaccharides mimicking the minimal intrachain or terminal epitopes of Bp and Bm LPS OAg . On the basis of these previous results, our current hypothesis is that oligosaccharides containing both the major internal and terminal epitopes of Bp and Bm LPS OAg could be suitable candidates for the development of vaccines against melioidosis and glanders. In this context, a synthetic pathway has been developed, which enables the preparation of tetrasaccharides related to Bp and Bm through a [1 + 1 + 1 + 1] glycosylation methodology via the use of orthogonal and participating protecting groups. Regio- and stereoselective reactions were conducted and anomerically pure oligosaccharides were prepared, highlighting the suitability of the developed method for the synthesis of complex oligosaccharides. Antigenicity and immunogenicity assays are soon to be conducted to assess their biological potential. Among other tests, the assembled oligosaccharides will be tested against monoclonal antibodies (mAbs) isolated from melioidosis Thai patients serum. The tetrasaccharides under study could find usefulness in the development of prophylactic measures against melioidosis and glanders, which are all the more relevant in the current global context.
- Cheng, A. C., Currie, B. J. Clin Microbiol Rev, 2005, 18, 383-416.
- Heiss, C. et al. Carbohydr Res, 2013, 381, 6-11.
- Tamigney Kenfack, M. et al. Nature Commun, 2017, 8, 115.