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Structural basis of metallo-β-lactamase inhibition by n-sulfamoylpyrrole-2-carboxylates

DOI: 10.1021/acsinfecdis.1c00104 DOI Help

Authors: Alistair J. M. Farley (University of Oxford) , Yuri Ermolovich (University of Copenhagen) , Karina Calvopina (University of Oxford) , Patrick Rabe (University of Oxford) , Tharindi Panduwawala (University of Oxford) , Jurgen Brem (University of Oxford) , Fredrik Björkling (University of Copenhagen) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases , VOL 1277

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 12346

Abstract: Metallo-β-lactamases (MBLs) can efficiently catalyze the hydrolysis of all classes of β-lactam antibiotics except monobactams. While serine-β-lactamase (SBL) inhibitors (e.g., clavulanic acid, avibactam) are established for clinical use, no such MBL inhibitors are available. We report on the synthesis and mechanism of inhibition of N-sulfamoylpyrrole-2-carboxylates (NSPCs) which are potent inhibitors of clinically relevant B1 subclass MBLs, including NDM-1. Crystallography reveals that the N-sulfamoyl NH2 group displaces the dizinc bridging hydroxide/water of the B1 MBLs. Comparison of crystal structures of an NSPC and taniborbactam (VRNX-5133), presently in Phase III clinical trials, shows similar binding modes for the NSPC and the cyclic boronate ring systems. The presence of an NSPC restores meropenem efficacy in clinically derived E. coli and K. pneumoniae blaNDM-1. The results support the potential of NSPCs and related compounds as efficient MBL inhibitors, though further optimization is required for their clinical development.

Journal Keywords: antimicrobial resistance; sulfonamide; metallo-β-lactamase; taniborbactam; NDM-1

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 31/05/2021 10:42

Discipline Tags:

Catalysis Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)