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Dynamically chiral phosphonic acid-type metallo-β-lactamase inhibitors
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai, Peoples R China..
UiT Arctic Univ Norway, Fac Sci & Technol, Dept Chem, Tromso, Norway..
Univ Med Ctr Hamburg Eppendorf UKE, Hamburg, Germany..
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2025 (English)In: Communications Chemistry, E-ISSN 2399-3669, Vol. 8, no 1, article id 119Article in journal (Refereed) Published
Abstract [en]

Antibiotic resistance is a growing global health threat that risks the lives of millions. Among the resistance mechanisms, that mediated by metallo-beta-lactamases is of particular concern as these bacterial enzymes dismantle most beta-lactam antibiotics, which are our widest applied and cheapest to produce antibiotic agents. So far, no clinically applicable metallo-beta-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-beta-lactamase enzymes NDM-1, VIM-2 and GIM-1, and are non-toxic to human cells. Mimicking the transition state of beta-lactam hydrolysis, they target the Zn ions of the metallo-beta-lactamase active site. As a unique feature, both of their stereoisomers bind metallo-beta-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.

Place, publisher, year, edition, pages
Springer Nature, 2025. Vol. 8, no 1, article id 119
National Category
Microbiology
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URN: urn:nbn:se:uu:diva-555791DOI: 10.1038/s42004-025-01510-5ISI: 001471182500001PubMedID: 40253435Scopus ID: 2-s2.0-105003195224OAI: oai:DiVA.org:uu-555791DiVA, id: diva2:1958107
Funder
Swedish National Infrastructure for Computing (SNIC), NAISS 2023/5-392Swedish National Infrastructure for Computing (SNIC), 2024/5-583Swedish Research Council, 2013-8804Swedish Research Council, 2024-05496Available from: 2025-05-13 Created: 2025-05-13 Last updated: 2025-05-13Bibliographically approved

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Gulyás, KingaDeufel, FritzWidersten, MikaelErdélyi, Máté

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