Cinnamide Derivatives of D-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa

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Sommer_0-321754.pdf(2.06 MB)
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2015
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Varrot, Annabelle
Audfray, Aymeric
Imberty, Anne
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urn:nbn:de:bsz:352-0-321754
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10.1002/open.201500162
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ChemistryOpen ; 4 (2015), 6. - pp. 756-767. - ISSN 2191-1355. - eISSN 2191-1363
Abstract
Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen with high antibiotic resistance. Its lectin LecB was identified as a virulence factor and is relevant in bacterial adhesion and biofilm formation. Inhibition of LecB with carbohydrate-based ligands results in a decrease in toxicity and biofilm formation. We recently discovered two classes of potent drug-like glycomimetic inhibitors, that is, sulfonamides and cinnamides of d-mannose. Here, we describe the chemical synthesis and biochemical evaluation of more than 20 derivatives with increased potency compared to the unsubstituted cinnamide. The structure–activity relationship (SAR) obtained and the extended biophysical characterization allowed the experimental determination of the binding mode of these cinnamides with LecB. The established surface binding mode now allows future rational structure-based drug design. Importantly, all glycomimetics tested showed extended receptor residence times with half-lives in the 5–20 min range, a prerequisite for therapeutic application. Thus, the glycomimetics described here provide an excellent basis for future development of anti-infectives against this multidrug-resistant pathogen.
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540 Chemistry
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carbohydrates, glycoconjugates, glycomimetics, LecB/PA-IIL, lectins
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ISO 690SOMMER, Roman, Dirk HAUCK, Annabelle VARROT, Stefanie WAGNER, Aymeric AUDFRAY, Andreas PRESTEL, Heiko M. MÖLLER, Anne IMBERTY, Alexander TITZ, 2015. Cinnamide Derivatives of D-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa. In: ChemistryOpen. 4(6), pp. 756-767. ISSN 2191-1355. eISSN 2191-1363. Available under: doi: 10.1002/open.201500162
BibTex
@article{Sommer2015Cinna-33436,
  year={2015},
  doi={10.1002/open.201500162},
  title={Cinnamide Derivatives of <sub>D</sub>-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa},
  number={6},
  volume={4},
  issn={2191-1355},
  journal={ChemistryOpen},
  pages={756--767},
  author={Sommer, Roman and Hauck, Dirk and Varrot, Annabelle and Wagner, Stefanie and Audfray, Aymeric and Prestel, Andreas and Möller, Heiko M. and Imberty, Anne and Titz, Alexander}
}
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