9F0S

VIM-2 in complex with GKV63 (5j) - dynamically chiral phosphonic acid-type metallo-beta-lactamase inhibitors

This is a non-PDB format compatible entry.

Summary for 9F0S

• Entry DOI: 10.2210/pdb9f0s/pdb
• Descriptor: Metallo-beta-lactamase type 2, FORMIC ACID, [(~{R})-(2-hydroxyphenyl)-(2-thiophen-3-ylethanoylamino)methyl]phosphonic acid, ... (5 entities in total)
• Functional Keywords: beta-lactamase, metallo-beta-lactamase, inhibitor, antibiotic
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 55933.75

Authors

Bosman, R.,Prester, A.,Bartels, K.,Gulyas, K.V.,Erdelyi, M.,Schulz, E.C. (deposition date: 2024-04-17, release date: 2025-04-30, Last modification date: 2025-05-07)

Primary citation

Gulyas, K.V.,Zhou, L.,Salamonsen, D.,Prester, A.,Bartels, K.,Bosman, R.,Haffke, P.,Li, J.,Tamasi, V.,Deufel, F.,Thoma, J.,Andersson Rasmussen, A.,Csala, M.,Schroder Leiros, H.K.,Xu, Z.,Widersten, M.,Rohde, H.,Schulz, E.C.,Zhu, W.,Erdelyi, M.
Dynamically chiral phosphonic acid-type metallo-beta-lactamase inhibitors.
Commun Chem, 8:119-119, 2025

PubMed 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.

PubMed: 40253435
DOI: 10.1038/s42004-025-01510-5

Experimental method

X-RAY DIFFRACTION (1.4 Å)