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.

Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases / 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.. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 10:1(2020), pp. 1-15. [10.1038/s41598-020-69431-y]

Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases

Spyrakis F.;Santucci M.;Tondi D.;Venturelli A.;Costi M. P.
2020-01-01

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.
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Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases / 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.. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 10:1(2020), pp. 1-15. [10.1038/s41598-020-69431-y]
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1216308
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