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.
Highlights
Antimicrobial resistance enables pathogens to resist to the effects of an antibiotic or drug that would usually kill them or limit their growth.[1]
Crystal structure analysis of the apo and the holo form of BC2L-C-nt demonstrated the presence of a druggable region in the vicinity of the fucoside binding site
The study indicates that the fragments bind in a newly identified binding region in BC2L-C-nt when the fucoside binding site is occupied
Summary
Antimicrobial resistance enables pathogens to resist to the effects of an antibiotic or drug that would usually kill them or limit their growth.[1]. Crystal structure of trimeric BC2L-C-nt complexed with, H-type 1 and Globo-H oligosaccharides are available,[14, 15] revealing three sugar binding sites located at the interface between neighboring chains (A, B, C), and separated by a distance of ~20 Å (Figure 1A).
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