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Gulyás KV, Zhou L, Salamonsen D, Prester A, Bartels K, Bosman R, Haffke P, Li J, Tamási V, Deufel F, Thoma J, Andersson Rasmussen A, Csala M, Schroder Leiros HK, Xu Z, Widersten M, Rohde H, Schulz EC, Zhu W, Erdélyi M
Commun Chem 8 (1) 119 [2025-04-19; online 2025-04-19]
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.
PubMed 40253435
DOI 10.1038/s42004-025-01510-5
Crossref 10.1038/s42004-025-01510-5
pmc: PMC12009420
pii: 10.1038/s42004-025-01510-5