6D1F

Crystal structure of NDM-1 complexed with compound 8

Summary for 6D1F

• Entry DOI: 10.2210/pdb6d1f/pdb
• Descriptor: Metallo-beta-lactamase type 2, ZINC ION, [(5,7-difluoro-2-oxo-2H-1-benzopyran-4-yl)methyl]phosphonic acid, ... (5 entities in total)
• Functional Keywords: beta-lactamase, carbapenemase, phosphonate, inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 25127.72

Authors

Pemberton, O.A.,Chen, Y. (deposition date: 2018-04-11, release date: 2019-04-17, Last modification date: 2023-10-04)

Primary citation

Pemberton, O.A.,Jaishankar, P.,Akhtar, A.,Adams, J.L.,Shaw, L.N.,Renslo, A.R.,Chen, Y.
Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.
J.Med.Chem., 62:8480-8496, 2019

PubMed 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 , exhibited low nM to low μM inhibition of KPC-2, NDM-1, and VIM-2. Compound 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.

PubMed: 31483651
DOI: 10.1021/acs.jmedchem.9b00728

Experimental method

X-RAY DIFFRACTION (1.15 Å)