Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases

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.