3-Bromopyruvate Shows Promise as Covalent Inhibitor of Antibiotic-Resistant Metallo-β-Lactamases
Researchers found that 3-bromopyruvate (3-BP), a hexokinase inhibitor, can covalently bind to and inhibit NDM-1 and NDM-5 metallo-β-lactamases, restoring carbapenem antibiotic effectiveness against resistant bacterial strains. This addresses a critical gap, as no metallo-β-lactamase inhibitors are currently approved for clinical use despite rising resistance to last-resort antibiotics. The findings suggest a new strategy for developing MBL inhibitors that could help combat multidrug-resistant infections.
A preprint study reports that 3-bromopyruvate (3-BP) selectively restored the antimicrobial activity of meropenem against carbapenem-resistant clinical and environmental bacterial isolates from Tanzania and Malawi that carry NDM-1 or NDM-5 genes. The research included three major pathogens: Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Mass spectrometry analysis revealed that 3-BP works through a covalent mechanism, reacting with an active site cysteine residue in these metallo-β-lactamases, rather than through the metal ion chelation approach used by most existing MBL inhibitors. The authors note that this covalent strategy has proven successful for serine β-lactamase inhibition and could inform future drug development. The work addresses an urgent clinical need, as metallo-β-lactamase-mediated resistance to carbapenems—antibiotics of last resort—is increasing globally with no approved inhibitors currently available.
What's missing
The study is a preprint and has not undergone peer review. The authors do not discuss potential toxicity of 3-BP in human systems, off-target effects, pharmacokinetic properties, or the feasibility of clinical translation. No information is provided on whether 3-BP's hexokinase inhibition activity would pose safety concerns in therapeutic use.
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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