PDBsum entry 6d1h

Hydrolase/hydrolase inhibitor

PDB id: 6d1h

Contents

Protein chain

229 a.a.

Ligands

KED

ACT ×2

Metals

_ZN ×2

Waters ×327

References listed in PDB file

Key reference

• Title: Heteroaryl phosphonates as noncovalent inhibitors of both serine- And metallocarbapenemases.
• Authors: O.A.Pemberton, P.Jaishankar, A.Akhtar, J.L.Adams, L.N.Shaw, A.R.Renslo, Y.Chen.
• Ref.: J Med Chem, 2019, 62, 8480-8496. [DOI no: 10.1021/acs.jmedchem.9b00728]
• PubMed id: 31483651

Abstract

Gram-negative pathogens expressing serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all β-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low μM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 μg/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery.