PDBsum entry 6d1h

Hydrolase/hydrolase inhibitor

PDB id: 6d1h

Contents

Protein chain

229 a.a.

Ligands

KED

ACT ×2

Metals

_ZN ×2

Waters ×327

PDB id:

6d1h

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of ndm-1 complexed with compound 11

Structure:

Metallo-beta-lactamase type 2. Chain: a. Synonym: b2 metallo-beta-lactamase,beta-lactamase type ii,metallo- beta-lactamase ndm-1,metallo-beta-lactamase type ii,new delhi metallo-beta-lactamase-1,ndm-1. Engineered: yes

Source:

Klebsiella pneumoniae. Organism_taxid: 573. Gene: blandm-1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.25Å R-factor: 0.148 R-free: 0.180

Authors:

O.A.Pemberton,Y.Chen

Key ref:

O.A.Pemberton et al. (2019). Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases. J Med Chem, 62, 8480-8496. PubMed id: 31483651 DOI: 10.1021/acs.jmedchem.9b00728

Date:

11-Apr-18 Release date: 17-Apr-19

Protein chain

C7C422  (BLAN1_KLEPN) -  Metallo-beta-lactamase type 2 from Klebsiella pneumoniae

Seq: 270 a.a.

Struc: 229 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: a beta-lactam + H2O = a substituted beta-amino acid
• Cofactor: Zn(2+)

DOI no: 10.1021/acs.jmedchem.9b00728

J Med Chem 62:8480-8496 (2019)

PubMed id: 31483651

Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.

O.A.Pemberton, P.Jaishankar, A.Akhtar, J.L.Adams, L.N.Shaw, A.R.Renslo, Y.Chen.

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.