Journal Article

PUBDB-2025-01464

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dynamically chiral phosphonic acid-type metallo-β-lactamase inhibitors

Gulyás, K. V. ; 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, H.-K. ; Xu, Z. ; Widersten, M. ; Rohde, H. ; Schulz, E. ; Zhu, W. ; Erdélyi, M. (Corresponding author)

2025
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s42004-025-01510-5  doi:10.3204/PUBDB-2025-01464

Abstract: 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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)458246365 - Zeitaufgelöste Strukturanalysde der extended spectrum Beta-Lactamase CTX-M-14 (458246365) (458246365)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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