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