Article (Scientific journals)
Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases
Spyrakis, F.; Santucci, M.; Maso, L. et al.
2020In Scientific Reports, 10 (1)
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Abstract :
[en] 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. © 2020, The Author(s).
Disciplines :
Microbiology
Author, co-author :
Spyrakis, F.;  Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy, Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, Turin, 10125, Italy
Santucci, M.;  Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy
Maso, L.;  Department of Biology, University of Padua, Viale G. Colombo 3, Padua, 35121, Italy
Cross, S.;  Molecular Discovery Limited, Centennial Avenue, Unit 501 Centennial Park, Borehamwood, Hertfordshire, WD6 3FG, United Kingdom
Gianquinto, E.;  Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, Turin, 10125, Italy
Sannio, F.;  Department of Medical Biotechnology, University of Siena, Viale Bracci 16, Siena, 53100, Italy
Verdirosa, F.;  Department of Medical Biotechnology, University of Siena, Viale Bracci 16, Siena, 53100, Italy
De Luca, F.;  Department of Medical Biotechnology, University of Siena, Viale Bracci 16, Siena, 53100, Italy
Docquier, Jean-Denis ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines
Cendron, L.;  Department of Biology, University of Padua, Viale G. Colombo 3, Padua, 35121, Italy
Tondi, D.;  Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy
Venturelli, A.;  TYDOCK PHARMA S.R.L., Strada Gherbella 294/b, Modena, 41126, Italy
Cruciani, G.;  Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, Perugia, 06123, Italy
Costi, M. P.;  Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy
More authors (4 more) Less
Language :
English
Title :
Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases
Publication date :
2020
Journal title :
Scientific Reports
eISSN :
2045-2322
Publisher :
Nature Research
Volume :
10
Issue :
1
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
EC: 286998
Funders :
CE - Commission Européenne [BE]
Available on ORBi :
since 11 November 2020

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