Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases

J Med Chem. 2019 Sep 26;62(18):8480-8496. doi: 10.1021/acs.jmedchem.9b00728. Epub 2019 Sep 13.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Enterobacter cloacae / drug effects
  • Escherichia coli / drug effects
  • HEK293 Cells
  • Humans
  • Imipenem / chemistry
  • Klebsiella pneumoniae / drug effects
  • Ligands
  • Microsomes, Liver / metabolism
  • Molecular Conformation
  • Organophosphonates / chemistry*
  • Pseudomonas aeruginosa / drug effects
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamases / chemistry
  • beta-Lactams / chemistry


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Ligands
  • Organophosphonates
  • beta-Lactamase Inhibitors
  • beta-Lactams
  • Imipenem
  • beta-lactamase KPC-2
  • beta-lactamase bla(vim-2)
  • beta-Lactamases
  • beta-lactamase NDM-1
  • carbapenemase