1. Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases
- Author
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Pemberton, Orville A, Jaishankar, Priyadarshini, Akhtar, Afroza, Adams, Jessie L, Shaw, Lindsey N, Renslo, Adam R, and Chen, Yu
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Clinical Sciences ,Emerging Infectious Diseases ,Antimicrobial Resistance ,Prevention ,Biodefense ,Vaccine Related ,Infectious Diseases ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Anti-Bacterial Agents ,Bacterial Proteins ,Crystallography ,X-Ray ,Drug Design ,Enterobacter cloacae ,Escherichia coli ,HEK293 Cells ,Humans ,Imipenem ,Klebsiella pneumoniae ,Ligands ,Microsomes ,Liver ,Molecular Conformation ,Organophosphonates ,Pseudomonas aeruginosa ,beta-Lactamase Inhibitors ,beta-Lactamases ,beta-Lactams ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - 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.
- Published
- 2019