Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes infections in patients suffering from chronic granulomatous diseases and cystic fibrosis. It displays significant morbidity and mortality due to extreme resistance to almost all clinically useful antibiotics. The bacterial lectin BC2L-C expressed in B. cenocepacia is an interesting drug target involved in bacterial adhesion and subsequent deadly infection to the host. We solved the first high resolution crystal structure of the apo form of the lectin N-terminal domain (BC2L-C-nt) and compared it with the ones complexed with carbohydrate ligands. Virtual screening of a small fragment library identified potential hits predicted to bind in the vicinity of the fucose binding site. A series of biophysical techniques and X-ray crystallographic screening were employed to validate the interaction of the hits with the protein domain. The X-ray structure of BC2L-C-nt complexed with one of the identified active fragments confirmed the ability of the site computationally identified to host drug-like fragments. The fragment affinity could be determined by titration microcalorimetry. These structure-based strategies further provide an opportunity to elaborate the fragments into high affinity anti-adhesive glycomimetics, as therapeutic agents against B. cenocepacia.

Prediction and Validation of a Druggable Site on Virulence Factor of Drug Resistant Burkholderia cenocepacia** / K. Lal, R. Bermeo Malo, J. Cramer, F. Vasile, B. Ernst, A. Imberty, A. Bernardi, A. Varrot, L. Belvisi. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 27:40(2021 Jul 16), pp. 10341-10348. [10.1002/chem.202100252]

Prediction and Validation of a Druggable Site on Virulence Factor of Drug Resistant Burkholderia cenocepacia**

K. Lal
Primo
;
R. Bermeo Malo
Secondo
;
F. Vasile;A. Bernardi
;
L. Belvisi
Ultimo
2021-07-16

Abstract

Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes infections in patients suffering from chronic granulomatous diseases and cystic fibrosis. It displays significant morbidity and mortality due to extreme resistance to almost all clinically useful antibiotics. The bacterial lectin BC2L-C expressed in B. cenocepacia is an interesting drug target involved in bacterial adhesion and subsequent deadly infection to the host. We solved the first high resolution crystal structure of the apo form of the lectin N-terminal domain (BC2L-C-nt) and compared it with the ones complexed with carbohydrate ligands. Virtual screening of a small fragment library identified potential hits predicted to bind in the vicinity of the fucose binding site. A series of biophysical techniques and X-ray crystallographic screening were employed to validate the interaction of the hits with the protein domain. The X-ray structure of BC2L-C-nt complexed with one of the identified active fragments confirmed the ability of the site computationally identified to host drug-like fragments. The fragment affinity could be determined by titration microcalorimetry. These structure-based strategies further provide an opportunity to elaborate the fragments into high affinity anti-adhesive glycomimetics, as therapeutic agents against B. cenocepacia.
Antimicrobial resistance; BC2L-C; Glycomimetics; Ligand design; Virtual screening
Settore CHIM/06 - Chimica Organica
H20MCITNIF17ABERN_01 - Multidisciplinary European Joint Doctorate in the Design and Development of Glyco Drugs (PhD4GlycoDrug) - BERNARDI, ANNA - H20MCITNIF - Horizon 2020_Marie Skłodowska-Curie actions-Innovative Training Network (ITN)/Individual Fellowships (IF) - 2017
26-mar-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/857951
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