Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa

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Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides l-fucose and d-mannose and conjugates thereof. Previously, d-mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because d-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended d-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl α-d-mannoside.

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540 Chemie
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Lectin, Pseudomonas aeruginosa, Inhibitor
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ISO 690HOFMANN, Anna, Roman SOMMER, Dirk HAUCK, Julia STIFEL, Inigo GÖTTKER-SCHNETMANN, Alexander TITZ, 2015. Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa. In: Carbohydrate Research. 2015, 412, pp. 34-42. ISSN 0008-6215. eISSN 1873-426X. Available under: doi: 10.1016/j.carres.2015.04.010
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@article{Hofmann2015Synth-31849,
  year={2015},
  doi={10.1016/j.carres.2015.04.010},
  title={Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa},
  volume={412},
  issn={0008-6215},
  journal={Carbohydrate Research},
  pages={34--42},
  author={Hofmann, Anna and Sommer, Roman and Hauck, Dirk and Stifel, Julia and Göttker-Schnetmann, Inigo and Titz, Alexander}
}
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