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Updated: May 16, 2026
08:58
Isolation and Identification of Waterborne Antibiotic-Resistant Bacteria and Molecular Characterization of their Antibiotic Resistance Genes
Published on: March 3, 2023
Development of Water-Trapping Pyrrole-2-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors
Monisha Singha1, Liam A Wilson1, Elisabete C C M Moura2
1Chemistry Research Laboratory, Department of Chemistry, and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
Journal of Medicinal Chemistry
|May 14, 2026
Summary
New metallo-β-lactamase (MBL) inhibitors show promise in combating antibiotic resistance. Pyrrole-2-carboxylic acid derivatives effectively inhibit key MBLs, potentially restoring carbapenem effectiveness against resistant Gram-negative bacteria.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Antimicrobial Resistance
Background:
- Antibiotic resistance, particularly from β-lactamases, compromises the efficacy of vital β-lactam antibiotics.
- While serine-β-lactamase inhibitors are available, effective metallo-β-lactamase (MBL) inhibitors are lacking for clinical use.
Purpose of the Study:
- To develop potent inhibitors for clinically significant B1 MBLs (NDM-1, VIM-1, VIM-2, IMP-1).
- To elucidate the inhibition mechanism of novel pyrrole-2-carboxylic acid derivatives against MBLs.
Main Methods:
- Structure-guided design and synthesis of pyrrole-2-carboxylic acid derivatives.
- Crystallographic studies to determine the binding mode and inhibition mechanism.
- In vitro testing of inhibitor efficacy against MBLs and in combination with carbapenems.
Main Results:
- Pyrrole-2-carboxylic acids were identified as potent inhibitors of B1 MBLs.
- Inhibition occurs via Zn(II) coordination and trapping of the bridging hydroxide ion in the active site.
- Derivatives enhanced carbapenem activity against MBL-producing Gram-negative bacteria.
Conclusions:
- Pyrrole-2-carboxylic acid derivatives represent a promising class of MBL inhibitors.
- Targeting structural/catalytic water molecules offers a strategy for selective metalloenzyme inhibition.
- This approach may overcome limitations of metal-chelation strategies and combat antibiotic resistance.
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