Chemical Biology Lecture: Carbohydrate-binding Proteins as Targets for Anti-Infectives and Diagnostics
- Dr. Alexander Titz (Helmholtz-Zentrum für Infektionsforschung)
- 12 April 2018
- Science Campus
2333 CC Leiden
Carbohydrate-binding Proteins as Targets for Anti-Infectives and Diagnostics: ESKAPE pathogen Pseudomonas aeruginosa and its Lectins
Pseudomonas aeruginosa causes a substantial number of nosocomial infections and is the leading cause of death of cystic fibrosis patients. This Gram-negative bacterium is highly resistant against antibiotics and further protects itself by forming a biofilm. Moreover, a high genomic variability among clinical isolates complicates therapy.
Its lectin LecB, a carbohydrate-binding protein, is a virulence factor and necessary for adhesion and biofilm formation. We analyzed the sequence of LecB variants in a library of clinical bacterial isolates and demonstrate that it can serve as a marker for strain family classification. LecB from the highly virulent model strain PA14 presents 13% sequence divergence with LecB from the well characterized PAO1 strain. Despite several amino acid variations at the carbohydrate binding site, glycan array analysis showed a comparable binding specificity for both variants.
Based on the crystal structures of the lectin with its glycan ligands, we dissected the contributions of individual functional groups to protein binding in a biophysics-guided approach. This knowledge was then used for the development of small and drug-like glycan-based molecules as LecB inhibitors as future anti-biofilm compounds in chronic P. aeruginosa infections.[3-7] Multiparameter optimization yielded potent anti-biofilm compounds for both strain types and oral availability in mice.
Thus, the different LecB sequences serve as marker for strain classification, but due to comparable ligand selectivity, LecB is a highly promising target for anti-virulence therapies, addressing members from both P. aeruginosa families, PAO1 and PA14.
In contrast, LecA binds galactosides with much lower affinity hampering therapeutic intervention at this target. Therefore, we have developed the first covalent inhibitor of a lectin and employed this LecA-specific irreversible inhibitor for LecA-dependent biofilm imagining of P. aeruginosa.
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- Sommer, R.; Exner, T.E.; Titz, A. PLoS ONE 2014, 9(11): e112822.
- Hauck, D.; Joachim, I.; Frommeyer, B.; Varrot, A.; Philipp, B.; Möller, H.M.; Imberty, A.; Exner, T.E.; Titz, A. ACS Chem. Biol. 2013, 8(8), 1775-1784.
- Beshr, G.; Sommer, R.; Hauck, D.; Siebert, D.C.B.; Hofmann, A.; Imberty, A.; Titz, A. Med. Chem. Commun. 2016, 7, 519-530.
- Sommer, R.; Wagner, S.; Rox, K.; Varrot, A.; Hauck, D.; Wamhoff, E.-C.; Schreiber, J.; Ryckmans, T.; Brunner, T.; Rademacher, C.; Hartmann, R. W.; Brönstrup, M.; Imberty, A.; Titz, A. J. Am. Chem. Soc. 2018, 140(7), 2537-2545.
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