Development of water-trapping pyrrole-2-carboxylic acids as broad-spectrum metallo-β-lactamase inhibitors

DOI: 10.1021/acs.jmedchem.5c03534

Authors: Monisha Singha (University of Oxford) , Liam A. Wilson (University of Oxford) , Elisabete C. C. M. Moura (University of Oxford) , Maria M. Trush (University of Oxford) , Karina Calvopina (University of Oxford) , Gurleen Kaur (University of Oxford) , Greta Zaborskytė (University of Oxford) , Toms Kalniņš (Latvian Institute of Organic Synthesis) , Tharindi Panduwawala (University of Oxford) , Matthew J. Bowen (University of Oxford) , Matthew J. Beech (University of Oxford) , Jurgen Brem (University of Oxford) , Peter J. Mchugh (University of Oxford) , Edgars Suna (Latvian Institute of Organic Synthesis) , Timothy R. Walsh (University of Oxford) , Christopher J. Schofield (University of Oxford) , Alistair J. M. Farley (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2026
Diamond Proposal Number(s): 31353

Abstract: Use of the clinically vital β-lactam antibiotics is increasingly compromised by resistance, commonly mediated by β-lactamases. While clinically used serine-β-lactamase (SBL) inhibitors have long been available, metallo-β-lactamase (MBL) inhibitors are not yet approved for clinical use. We report the structure-guided development of pyrrole-2-carboxylic acid derivatives as potent inhibitors of the clinically important di-Zn(II) ion containing B1 MBLs (NDM-1, VIM-1, VIM-2, IMP-1). Crystallographic studies reveal the pyrrole-2-carboxylic acids inhibit B1 MBLs via active site Zn(II)-coordination of the inhibitor carboxylate and trapping of the di-Zn(II) ion bridging hydroxide, the latter of which reacts with the substrate β-lactam ring during hydrolysis. Appropriately derivatized pyrrole-2-carboxylic acids enhance the activity of carbapenems against MBL producing Gram-negative clinical isolates. The results support further development of metalloenzyme inhibitors that exploit binding to structural or catalytically important water molecules, an approach which may help in achieving selectivity over other metalloenzymes compared to metal-chelation based approaches.

Diamond Keywords: Bacteria; Enzymes

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


Instruments: I03-Macromolecular Crystallography

Added On: 15/05/2026 07:28

Documents:
development-of-water-trapping-pyrrole-2-carboxylic-acids-as-broad-spectrum-metallo-%CE%B2-lactamase-inhibitors.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)