Synthesis and biological evaluation of immunogenic teichoic acids fragments

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Synthesis and biological evaluation of immunogenic teichoic acids fragments

Francesca Berni 1 , Angela van Diepen 2 , Ermina Kalfopoulou 3 , Anna Gimeno 4 , Johannes Huebner 3 , Herman Overkleeft 1 , Cornelis Hokke 2 , Jesus Barbero 4 , Gijs van der Marel 1 , Jeroen Codee 1

1 Leiden University, Leiden, The Netherlands, 2 Leiden university medical center, Leiden, The Netherlands, 3 Ludwig-Maximilians-University, Munich, Germany, 4 CIC bioGUNE, Derio, Spain

Teichoic acids (TAs) are found abundantly as cell wall components of the majority of Gram-positive bacteria.[1] Since the arising of antibiotic resistance bacterial strains in nosocomial infections, TAs have been identified as possible antigen candidate in vaccine development. Structurally TAs from S. aureus, E. faecalis and E. faecium share a glycerol-phosphate backbone that can be decorated with different glucosyl substituents. Both native and synthetic glycerol-phosphate TAs have been found to be immunogenic and to raised opsonic antibodies ensuring protection in both active and passive immunization.[2]

To further understand the binding between teichoic acids and antibodies, a new set of well-defined TAs hexamers was developed. These fragments differ for the position of a glucose moiety along the glycerol-phosphate backbone and for the stereochemistry of the glycerol unit. Using molecular dynamics, different population distributions of low energy conformers were observed among the structural similar diastereoisomers, revealing possible different spatial and chemical properties. Indeed, using a microarray tool,3 the preferential binding of polyclonal antibodies ( raised against native TAs from E. faecalis or against a synthetic well-defined glycoconjugate) was affected not only upon the position of the carbohydrate moiety but also for the defined glycerol stereogenic center. Finally, STD-NMR experiments were employed to map the epitope of a glucosyl glycerol-phosphate hexamer and its related monoclonal antibody.

Figure: Synthesis of teichoic acids fragments. Evaluation using molecular dynamics, microarray and STD experiments.

A) Neuhaus, F. C.; Baddiley, J. Microbiol. Mol. Biol. Rev. 2003, 67, 686–723.B) Weidenmaier, C.; Peschel, A. Nat. Rev. Microbiol. 2008, 6, 276–287.

Laverde, D.; Wobser, D.; Romero-Saavedra, F.; Hogendorf, W.; van der Marel, G.; Berthold, M.; Kropec, A.; Codee, J.; Huebner, J. PLoS One 2014, 9, e110953.

D. van der Es, F. Berni, J. D. C. Codée, Chem. Eur. J., 2018, 24, 4014-4018

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