Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases
Document Type
Article
Publication Date
2019
Digital Object Identifier (DOI)
https://doi.org/10.1021/acs.jmedchem.9b00728
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.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Journal of Medicinal Chemistry, v. 62, issue 18, p. 8480-8496
Scholar Commons Citation
Pemberton, Orville A.; Jaishankar, Priyadarshini; Akhtar, Afroza; Adams, Jessie L.; Shaw, Lindsey N.; Renslo, Adam R.; and Chen, Yu, "Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases" (2019). Molecular Medicine Faculty Publications. 69.
https://digitalcommons.usf.edu/mme_facpub/69
