Pré-Publication, Document De Travail Année : 2020

Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases of classes A, B and D

Laetitia A Nguyen
Alain Pruvost

Résumé

The rise of resistances in Gram negative bacteria is reaching an extremely worrying situation 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-analogs 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-betalactamase 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 this compound can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A, B and D, but also β-lactamases ofall four classes (A, B, C and D). Our results pave the way for the development of a newstructurally originalfamily of non-covalent broad-spectrum inhibitors of β-lactamases.

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hal-02998861 , version 1 (10-11-2020)

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Eugénie Romero, Saoussen Oueslati, Mohamed Benchekroun, Agathe 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 of classes A, B and D. 2020. ⟨hal-02998861⟩
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