7AYJ

Metallo beta-lactamse Vim-1 with a sulfamoyl inhibitor.

Summary for 7AYJ

• Entry DOI: 10.2210/pdb7ayj/pdb
• Descriptor: Beta-lactamase VIM-1, ZINC ION, 3-(4-fluorophenyl)-1-sulfamoyl-pyrrole-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: vim1, metallo beta lactamse, inhibition, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 27345.84

Authors

Farley, A.J.M.,Ermolovich, I.,Calvopina, K.,Rabe, P.,Brem, J.,Schofield, C.J. (deposition date: 2020-11-12, release date: 2021-05-12, Last modification date: 2024-11-20)

Primary citation

Farley, A.J.M.,Ermolovich, Y.,Calvopina, K.,Rabe, P.,Panduwawala, T.,Brem, J.,Bjorkling, F.,Schofield, C.J.
Structural Basis of Metallo-beta-lactamase Inhibition by N -Sulfamoylpyrrole-2-carboxylates.
Acs Infect Dis., 7:1809-1817, 2021

PubMed 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 -sulfamoylpyrrole-2-carboxylates (NSPCs) which are potent inhibitors of clinically relevant B1 subclass MBLs, including NDM-1. Crystallography reveals that the -sulfamoyl NH 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 and 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.

PubMed: 34003651
DOI: 10.1021/acsinfecdis.1c00104

Experimental method

X-RAY DIFFRACTION (1.21 Å)