Open AccessStructural Basis of Metallo-β-lactamase Inhibition byN-Sulfamoylpyrrole-2-carboxylates
Author(s) -
Alistair J. M. Farley,
Yurii V. Ermolovich,
Karina Calvopiña,
Patrick Rabe,
Tharindi Panduwawala,
Jürgen Brem,
Fredrik Björkling,
Christopher J. Schofield
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.1c00104
Subject(s) - clavulanic acid , serine , docking (animal) , beta lactamase inhibitors , stereochemistry , antibiotics , chemistry , subclass , biochemistry , combinatorial chemistry , microbiology and biotechnology , biology , enzyme , amoxicillin , medicine , nursing , antibody , immunology
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 NH 2 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 bla NDM-1. The results support the potential of NSPCs and related compounds as efficient MBL inhibitors, though further optimization is required for their clinical development.