Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 664.97 Food technology

Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019

Mô tả vật lý: Size: p. 8480-8496 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 261844

Gram-negative pathogens expressing serine ?-lactamases (SBLs) and metallo-?-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all ?-lactam antibiotics. In this study 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 ?M 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 ?g/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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