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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

submitted on 25.02.2020, 11:53 and posted on 25.02.2020, 13:32 by Eugénie Romero, Saoussen Oueslati, Mohamed Benchekroun, Agathe C. A. D’Hollander, Sandrine Ventre, Kamsana Vijayakumar, Corinne Minard, Cynthia Exilie, Linda Tlili, Pascal Retailleau, Agustin Zavala, Eddy Elisée, Edithe Selwa, Laetitia A. Nguyen, Alain Pruvost, Thierry Naas, Bogdan I. Iorga, Robert Dodd, Kevin Cariou
The increasingly worrisome situation of antimicrobial resistances has pushed synthetic chemists to design original molecules that can fight these resistances. To do so, inhibiting β-lactamases, one of the main modes of resistance to β-lactam antibiotics, is one of the most sought-after strategies, as recently evidenced by the development and approval of avibactam, relabactam and vaborbactam. Yet molecules able to inhibit simultaneously β-lactamases belonging to different molecular classes remain scarce and currently there is no metallo-β-lactamase inhibitor approved for clinical use. Having recently developed a synthetic methodology to access imino-analogues of β-lactams (Chem. – Eur. J. 2017, 23, 12991,see ref) we decided to evaluate them as potential β-lactamase inhibitors and specifically against carbapenemases, which can hydrolyze and inactivate penicillins, cephalosporins and carbapenems. Herein we eport our findings that show that our newly developed family of molecules are indeed excellent β-lactamase inhibitors and that our lead compound can inhibit NDM-1 (0.1 µM), KPC-2 (0.4 µM), and OXA-48 (0.6 µM) even though these three enzymes belong to three different molecular classes of carbapenemases. This lead compound also inhibits the ESBL CTX-M-15 and the cephalosporinase CMY-2, it is metabolically stable, and can repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1.


LERMIT, grant ANR-10-LABX-33 under the program Investissements d’Avenir ANR-11-IDEX-0003-01

FCS Campus Paris-Saclay pre-maturation program (project Inhibase)

the SATT Paris-Saclay (project CARBAMAT)

JPIAMR transnational project DesInMBL (grant ANR-14-JAMR-0002)

Région Ile-de-France (DIM Malinf)


Email Address of Submitting Author


Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest