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

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.