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

Lal, Kanhaya and Bermeo, Rafael and Cramer, Jonathan and Vasile, Francesca and Ernst, Beat and Imberty, Anne and Bernardi, Anna and Varrot, Annabelle and Belvisi, Laura. (2021) Prediction and Validation of a Druggable Site on Virulence Factor of Drug Resistant Burkholderia cenocepacia*. Chemistry - A European Journal, 27 (40). pp. 10341-10348.

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Official URL: https://edoc.unibas.ch/84303/

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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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Ernst, Beat and Cramer, Jonathan
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Sep 2021 08:41
Deposited On:06 Sep 2021 08:41

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