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)

Abstract

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Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors

“…In addition, compound 28 possesses an excellent stability profile with a Cl int of 2.0–13.9 μL/min/mg protein in mouse hepatic cells. A relatively low toxicity in the case of 28 was observed against MRC-5 and HCT116 cells with an IC 50 range of 20–30 μM . Importantly, compound 28 also potentiated the effect of imipenem against E. coli producing NDM-1, bringing MIC down to the intermediate/resistant limit.…”

“…A relatively low toxicity in the case of 28 was observed against MRC-5 and HCT116 cells with an IC 50 range of 20−30 μM. 106 Importantly, compound 28 also potentiated the effect of imipenem against E. coli producing NDM-1, bringing MIC down to the intermediate/resistant limit.…”

“…Given that the azetidinimines, imino-analogues of β-lactams, have a structural similarity with β-lactams, Romero et al developed a series of azetidinimines ( 23 – 28 , Figure ) by replacing the ketene with the in-situ-generated iminoketene and evaluated their inhibitory potential against carbapenemases . The most active compound 28 manifested sub-micromolar broad-spectrum inhibition of carbapenemases from all three clinically relevant β-lactamase classes: class A KPC-2 (0.28 μM), class D OXA-48 (0.07 μM), and class B NDM-1 (0.07 μM).…”

“…The aromatic hydroxyl of azetidinimine ( 23 – 28 ) as a bridge ligand is connected between two Zn­(II) ions in the active-site pocket of NDM-1. The aromatic hydroxyl binds to the active-site catalytic residues Ser70 and Lys73 of KPC-2 and OXA-48 through the formation of H bonds resulting in the inhibition of serine carbapenemases . The tetrazole moiety of compounds 39 – 42 forms three H bonds with key residues Ser130, Thr235, and Thr237 in the active-site pocket of serine carbapenemases.…”

“…The aromatic hydroxyl binds to the active-site catalytic residues Ser70 and Lys73 of KPC-2 and OXA-48 through the formation of H bonds resulting in the inhibition of serine carbapenemases. 106 The tetrazole moiety of compounds 39−42 forms three H bonds with key residues Ser130, Thr235, and Thr237 in the active-site pocket of serine carbapenemases. When inhibiting metallo-carbapenemases, the tetrazole group coordinates one of the Zn(II) ions and forms two H bonds with key residue Lys211 and Asn220 (NDM-1) 112 and, more generally, Lys224 and Asn233 (BBL standard numbering).…”