Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D)

Eugénie Romero (1) , Saoussen Oueslati (2, 3) , Mohamed Benchekroun (1) , Agathe C.A. D’hollander (1) , Sandrine Ventre (1) , Kamsana Vijayakumar (1) , Corinne Minard (1) , Cynthia Exilie (2) , Linda Tlili (3, 2) , Pascal Retailleau (1) , Agustin Zavala (1) , Eddy Elisée (1) , Edithe Selwa (1) , Laetitia Nguyen (4) , Alain Pruvost (4) , Thierry Naas (3, 5) , Bogdan Iorga (1) , Robert Dodd (1) , Kevin Cariou (1)

1 ICSN - Institut de Chimie des Substances Naturelles
2 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
3 IMVA-HB - Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes
4 MTS - Médicaments et Technologies pour la Santé
5 EERA - Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance

The occurrence of resistances in Gram negative bacteria is steadily increasing to reach extremely worrying levels and one of the main causes of resistance is the massive spread of very efficient β-lactamases which render most β-lactam antibiotics useless. Herein, we report the development of a series of imino-analogues of β-lactams (namely azetidinimines) as efficient non-covalent inhibitors of β-lactamases. Despite the structural and mechanistic differences between serine-β-lactamases KPC-2 and OXA-48 and metallo-β-lactamase NDM-1, all three enzymes can be inhibited at a submicromolar level by compound 7dfm, which can also repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1. We show that 7dfm can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A (KPC-2), B (NDM-1) and D (OXA-48) with Ki’s below 0.3 μM, but also the cephalosporinase CMY-2 (class C, 86% inhibition at 10 μM). Our results pave the way for the development of a new structurally original family of non-covalent broad-spectrum inhibitors of β-lactamases.

Mots clés: Bacterial resistance; Carbapenemase inhibitors; Azetidinimines; Ynamides; NDM-1; OXA-48; KPC-2

Domaines: Chimie thérapeutique

Eugénie Romero, Saoussen Oueslati, Mohamed Benchekroun, Agathe C.A. D’hollander, Sandrine Ventre, et al.. Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D). European Journal of Medicinal Chemistry, 2021, 219, ⟨10.1016/j.ejmech.2021.113418⟩. ⟨hal-03227989⟩