6TGI

Crystal structure of VIM-2 in complex with triazole-based inhibitor OP24

Summary for 6TGI

• Entry DOI: 10.2210/pdb6tgi/pdb
• Descriptor: Vim-1, ZINC ION, FORMIC ACID, ... (5 entities in total)
• Functional Keywords: new delhi metallo-beta-lactamase, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 53560.15

Authors

Maso, L.,Spirakis, F.,Santucci, M.,Simon, C.,Docquier, J.D.,Cruciani, G.,Costi, M.P.,Tondi, D.,Cendron, L. (deposition date: 2019-11-15, release date: 2020-10-14, Last modification date: 2024-01-24)

Primary citation

Spyrakis, F.,Santucci, M.,Maso, L.,Cross, S.,Gianquinto, E.,Sannio, F.,Verdirosa, F.,De Luca, F.,Docquier, J.D.,Cendron, L.,Tondi, D.,Venturelli, A.,Cruciani, G.,Costi, M.P.
Virtual screening identifies broad-spectrum beta-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases.
Sci Rep, 10:12763-12763, 2020

PubMed Abstract: Bacteria are known to evade β-lactam antibiotic action by producing β-lactamases (BLs), including carbapenemases, which are able to hydrolyze nearly all available β-lactams. The production of BLs represents one of the best known and most targeted mechanisms of resistance in bacteria. We have performed the parallel screening of commercially available compounds against a panel of clinically relevant BLs: class A CTX-M-15 and KPC-2, subclass B1 NDM-1 and VIM-2 MBLs, and the class C P. aeruginosa AmpC. The results show that all BLs prefer scaffolds having electron pair donors: KPC-2 is preferentially inhibited by sulfonamide and tetrazole-based derivatives, NDM-1 by compounds bearing a thiol, a thiosemicarbazide or thiosemicarbazone moiety, while VIM-2 by triazole-containing molecules. Few broad-spectrum BLs inhibitors were identified; among these, compound 40 potentiates imipenem activity against an NDM-1-producing E. coli clinical strain. The binary complexes of the two most promising compounds binding NDM-1 and VIM-2 were obtained at high resolution, providing strong insights to improve molecular docking simulations, especially regarding the interaction of MBLs with inhibitors.

PubMed: 32728062
DOI: 10.1038/s41598-020-69431-y

Experimental method

X-RAY DIFFRACTION (1.6 Å)