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).

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. [Display omitted] • Forty azetidinimines synthesized and evaluated for their activity against carbapenemases. • Several compounds are submicromolar inhibitors of both MBLs (NDM-1) and SBLs of class A (KPC-2) and D (OXA-48). • One compound is also active against 4 other MBLs (NDM-4, NDM-7, NDM-9 and VIM-1), CTX-M-15 (class A) and CMY-2 (class C). • The same compound can repotentiate imipenem against a NDM-1-producing clinical isolate of E. coli. [ABSTRACT FROM AUTHOR]