3-Bromopyruvate Shows Promise as Covalent Inhibitor of Antibiotic-Resistant Metallo-β-Lactamases
Researchers found that 3-bromopyruvate (3-BP), a known hexokinase inhibitor, can covalently inhibit NDM-1 and NDM-5 metallo-β-lactamases and restore meropenem's effectiveness against carbapenem-resistant bacteria. The compound was tested against clinical and environmental isolates from Tanzania and Malawi, selectively targeting strains carrying NDM genes but not those with serine β-lactamases. This matters because no metallo-β-lactamase inhibitors are currently approved for clinical use, and carbapenem resistance is a growing global health threat.
A preprint study on bioRxiv reports that 3-bromopyruvate (3-BP) selectively restores the antimicrobial activity of meropenem against carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii strains harboring NDM-1 or NDM-5 genes. The bacterial isolates were sourced from clinical and environmental settings in Tanzania and Malawi, reflecting real-world resistance patterns in sub-Saharan Africa. Mass spectrometry analysis supports a covalent mechanism in which 3-BP reacts with an active-site cysteine residue in both NDM-1 and NDM-5, distinguishing it from most reported metallo-β-lactamase inhibitors, which act primarily through zinc ion chelation. Crucially, 3-BP showed no activity against strains carrying serine β-lactamases, indicating selectivity for the metallo-β-lactamase class. The authors suggest these findings could catalyze broader research into covalently reacting MBL inhibitors, a strategy already proven successful against serine β-lactamases. Currently, no MBL inhibitors have received clinical approval, making this a potentially significant mechanistic lead.
What's missing
As a preprint, this study has not yet undergone peer review. Key limitations not addressed include: in vivo efficacy and toxicity data for 3-BP in animal models, the therapeutic window given 3-BP's known cytotoxicity in mammalian cells (as a hexokinase inhibitor), and pharmacokinetic properties.
What different sources said
- bioRxivCenter
Covalent Inhibition of New Delhi Metallo-β-Lactamases NDM-1 and NDM-5 by 3-Bromopyruvate
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