Dynamically chiral phosphonic acid-type metallo-β-lactamase inhibitors
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.
Authors
- Robert Bosman (ORCID: https://orcid.org/0000-0002-9939-602X)
- Hanna‐Kirsti S. Leiros (ORCID: https://orcid.org/0000-0002-2726-6322)
- Anna Andersson Rasmussen
- Viola Tamási (ORCID: https://orcid.org/0000-0001-7419-5603)
- Kim Bartels (ORCID: https://orcid.org/0000-0002-7980-1913)
- Máté Erdélyi (ORCID: https://orcid.org/0000-0003-0359-5970)
- Fritz Deufel (ORCID: https://orcid.org/0000-0003-4910-3388)
- Johannes Thoma (ORCID: https://orcid.org/0000-0003-3584-8274)
- Kinga Virág Gulyás
- Liping Zhou (ORCID: https://orcid.org/0000-0001-7750-7262)
- Holger Rohde (ORCID: https://orcid.org/0000-0001-8587-4433)
- Eike C. Schulz (ORCID: https://orcid.org/0000-0002-1685-8605)
- Weiliang Zhu (ORCID: https://orcid.org/0000-0001-6699-5299)
- Mikael Widersten (ORCID: https://orcid.org/0000-0002-3203-3793)
- Miklós Csala (ORCID: https://orcid.org/0000-0002-3829-4361)
- Andreas Prester (ORCID: https://orcid.org/0000-0003-2738-7682)
- Zhijian Xu (ORCID: https://orcid.org/0000-0002-3063-8473)
- Jintian Li (ORCID: https://orcid.org/0000-0002-0848-5730)
- Daniel Salamonsen
- Paul Haffke
Institutions
- Semmelweis University (HU)
- Uppsala University (SE)
- Universität Hamburg (DE)
- Lund University (SE)
- Chinese Academy of Sciences (CN)
- Science for Life Laboratory (SE)
- University Medical Center Hamburg-Eppendorf (DE)
- Shanghai Institute of Materia Medica (CN)
- CNR de la Résistance aux Antibiotiques (FR)
- Max Planck Institute for the Structure and Dynamics of Matter (DE)
- UiT The Arctic University of Norway (NO)
- University of Gothenburg (SE)
Publication Details
- Journal
- Communications Chemistry
- Published
- 2025-04-19
- DOI
- https://doi.org/10.1038/s42004-025-01510-5
- Citations
- 2
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 1.18
Funders
- Åke Wiberg Stiftelse
- Deutsche Forschungsgemeinschaft
- Swedish Foundation for International Cooperation in Research and Higher Education
- National Natural Science Foundation of China
- National Science Council
- Bundesministerium für Bildung und Forschung
- Lunds Universitet
- Svenska Sällskapet för Medicinsk Forskning
- Max-Planck-Gesellschaft
- Vetenskapsrådet
- Uppsala Universitet
- Deutsches Elektronen-Synchrotron
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap