2025/04/19 by Kinga Virág Gulyás, Liping Zhou, Daniel Salamonsen +17 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Antibiotic Resistance in Bacteria #Pneumocystis jirovecii pneumonia detection and treatment #Pneumonia and Respiratory Infections
paper · pdf · doi:10.1038/s42004-025-01510-5
openalex publication_date 2025/04/19 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
Antibiotic resistance is a growing global health threat that risks the lives of millions. Among the resistance mechanisms, that mediated by metallo-β-lactamases is of particular concern as these bacterial enzymes dismantle most β-lactam antibiotics, which are our widest applied and cheapest to produce antibiotic agents. So far, no clinically applicable metallo-β-lactamase inhibitors are available. Aiming to adapt to structural variations, we introduce the inhibitor concept: dynamically chiral phosphonic acids. We demonstrate that they are straightforward to synthesize, penetrate bacterial membranes, inhibit the metallo-β-lactamase enzymes NDM-1, VIM-2 and GIM-1, and are non-toxic to human cells. Mimicking the transition state of β-lactam hydrolysis, they target the Zn ions of the metallo-β-lactamase active site. As a unique feature, both of their stereoisomers bind metallo-β-lactamases, which provides them unparalleled adaptability to the structural diversity of these enzymes, and may allow them to hamper bacteria's ability for resistance development.