NMR Characterization of the Influence of Zinc(II) Ions on the Structural and Dynamic Behavior of the New Delhi Metallo-β-Lactamase-1 and on the Binding with Flavonols as Inhibitors

Gwladys Rivière (1) , Saoussen Oueslati (2) , Maud Gayral (3) , Jean-Bernard Créchet (4) , Naïma Nhiri (1) , Eric Jacquet (1) , Jean-Christophe Cintrat (5) , François Giraud (1) , Carine van Heijenoort (1) , Ewen Lescop (1) , Stéphanie Pethe (3) , Bogdan I. Iorga (1) , Thierry Naas (2) , Eric Guittet (1) , Nelly Morellet (1)

1 ICSN - Institut de Chimie des Substances Naturelles
2 Structure, Dynamique, Fonction Et Expression Des Beta-Lactamases À Large Spectre
3 ICMMO - Institut de Chimie Moléculaire et des Matériaux d'Orsay
4 X - École polytechnique
5 SCBM - Service de Chimie Bio-Organique et de Marquage

New Delhi metallo-β-lactamase-1 (NDM-1) has recently emerged as a global threat because of its ability to confer resistance to all common β-lactam antibiotics. Understanding the molecular basis of β-lactam hydrolysis by NDM is crucial for designing NDM inhibitors or β-lactams resistant to their hydrolysis. In this study, for the first time, NMR was used to study the influence of Zn(II) ions on the dynamic behavior of NDM-1. Our results highlighted that the binding of Zn(II) in the NDM-1 active site induced several structural and dynamic changes on active site loop 2 (ASL2) and L9 loops and on helix α2. We subsequently studied the interaction of several flavonols: morin, quercetin, and myricetin were identified as natural and specific inhibitors of NDM-1. Quercetin conjugates were also synthesized in an attempt to increase the solubility and bioavailability. Our NMR investigations on NDM-1/flavonol interactions highlighted that both Zn(II) ions and the residues of the NDM-1 ASL1, ASL2, and ASL4 loops are involved in the binding of flavonols. This is the first NMR interaction study of NDM-1/inhibitors, and the models generated using HADDOCK will be useful for the rational design of more active inhibitors, directed against NDM-1.

Domaines: Bactériologie; Biologie structurale [q-bio.BM]

Gwladys Rivière, Saoussen Oueslati, Maud Gayral, Jean-Bernard Créchet, Naïma Nhiri, et al.. NMR Characterization of the Influence of Zinc(II) Ions on the Structural and Dynamic Behavior of the New Delhi Metallo-β-Lactamase-1 and on the Binding with Flavonols as Inhibitors. ACS Omega, 2020, 5 (18), pp.10466-10480. ⟨10.1021/acsomega.0c00590⟩. ⟨hal-02604220⟩