Total Synthesis of Five Lipoteichoic acids of Clostridium difficile

Abstract

The emergence of hypervirulent resistant strains have made Clostridium difficile a notorious nosocomial pathogen and has resulted in a renewed interest in preventive strategies, such as vaccines based on (synthetic) cell wall antigens. Recently, the structure of the lipoteichoic acid (LTA) of this species has been elucidated. Additionally, this LTA was found to induce the formation of protective antibodies against C. difficile in rabbits and mice. The LTA from C. difficile is isolated as a microheterogenous mixture, differing in size and composition, impeding any structure-activity relationship studies. To ensure reliable biological results, pure and well-defined synthetic samples are required. In this work the total synthesis of LTAs from C. difficile with defined chain length is described and the initial biological results are presented.

Synthetic Lipoteichoic Acid Glycans Are Potential Vaccine Candidates to Protect from Clostridium difficile Infections

“…polymer that differs from most other LTAs bearing a conserved poly-1,3-(glycerolphosphate) backbone (Neuhaus and Baddiley, 2003). Our data are in accordance with a recent study that found no activation of innate immune markers in PBMCs upon exposure to C. difficile LTA (Hogendorf et al, 2014).…”

“…LTAs of various Gram-positive bacteria activate innate immunity in leukocytes by engaging toll-like receptor 2 (TLR2) that leads to the release of immunoregulatory cytokines including tumor necrosis factor alpha (TNF-a) and interleukins (ILs) (Schwandner et al, 1999). In contrast, a recent study showed that synthetic C. difficile LTA glycans did not activate peripheral blood leukocytes (PBMCs) (Hogendorf et al, 2014). PBMCs contain less than 1% dendritic cells (DCs) (Haller Hasskamp et al, 2005).…”

Synthesis of Defined and Functionalized Glycans of Lipoteichoic Acid: A Cell Surface Polysaccharide from Clostridium difficile

“…24 Pedersen and co-workers synthesized some LTA analogs that contained the lipidated core trisaccharide and repeating unit and used them to explore the noninnate immunity pathway. 22 Furthermore, it was shown that the protein conjugates of deacylated LTA could elicit antibodies to recognize both C. dif f icile and other Clostridium strains. 26 These results have highlighted the LTA glycan and related oligosaccharides as promising antigens for the development of C. dif f icile vaccines.…”

“…Seeberger and co-workers 21 described the synthesis of an LTA repeating unit and its oligomers and used them to study an LTA-based vaccine. 24 Pedersen and co-workers 22 reported the synthesis of some LTA analogs that contained all key structural components of LTA. Our synthesis diverged from these reports in that different building blocks and glycosylation methods were used to construct the repeating unit and the core trisaccharide, which gave improved overall synthetic efficiency.…”

“…Vaccination is one strategy for the effective control of CDIs. − In the development of vaccines, most present efforts have been focused on C. difficile toxins, such as toxin A and toxin B, as target antigens. , Recently, the cell surface polysaccharides of C. difficile , including PS-I, PS-II, and lipoteichoic acid (LTA, also called PS-III), , have been characterized and identified as promising antigenic epitopes for prophylactic vaccine development. Accordingly, several oligosaccharides related to these polysaccharides have been synthesized − and utilized to explore conjugate vaccines that have exhibited encouraging results. ,,,, The structure of the LTA (Figure ) from C. difficile and Peptostreptococcus anaerobius as well is comprised of a lipophilic diacylglycerol β-1,6-triglucoside core and many repeating d -glyceric acid α-1,4-diglucosaminoside units, which are stitched together via phosphodiester bridges . Seeberger and co-workers described the first synthesis of the repeating unit of this LTA and its oligomers and found that they were recognized by antibodies from C. difficile patients.…”