Heteroaryl phosphonates as non-covalent inhibitors of both serine and metallo-carbapenemases.

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ID: 36153
2019
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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 non-covalent 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.
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pemberton2019heteroaryljournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Pemberton, Orville Antonio;Jaishankar, Priyadarshini;Akhtar, Afroza;Adams, Jessie L;Shaw, Lindsey N;Renslo, Adam R;Chen, Yu;
Journal Journal of medicinal chemistry
Year 2019
DOI
10.1021/acs.jmedchem.9b00728
URL
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