8B20

NDM-1 metallo-beta-lactamase in complex with triazole-based inhibitor CP57

Summary for 8B20

• Entry DOI: 10.2210/pdb8b20/pdb
• Related: 8B1W 8B1Z
• Descriptor: Beta-lactamase NDM-1, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: beta-lactamase, antibiotic resistance, beta-lactamase inhibitor, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 52462.37

Authors

Vascon, F.,Lazzarato, L.,Bersani, M.,Gianquinto, E.,Docquier, J.D.,Spyrakis, F.,Tondi, D.,Cendron, L. (deposition date: 2022-09-12, release date: 2023-12-27, Last modification date: 2024-03-20)

Primary citation

Bersani, M.,Failla, M.,Vascon, F.,Gianquinto, E.,Bertarini, L.,Baroni, M.,Cruciani, G.,Verdirosa, F.,Sannio, F.,Docquier, J.D.,Cendron, L.,Spyrakis, F.,Lazzarato, L.,Tondi, D.
Structure-Based Optimization of 1,2,4-Triazole-3-Thione Derivatives: Improving Inhibition of NDM-/VIM-Type Metallo-beta-Lactamases and Synergistic Activity on Resistant Bacteria.
Pharmaceuticals, 16:-, 2023

PubMed Abstract: The worldwide emergence and dissemination of Gram-negative bacteria expressing metallo-β-lactamases (MBLs) menace the efficacy of all β-lactam antibiotics, including carbapenems, a last-line treatment usually restricted to severe pneumonia and urinary tract infections. Nonetheless, no MBL inhibitor is yet available in therapy. We previously identified a series of 1,2,4-triazole-3-thione derivatives acting as micromolar inhibitors of MBLs in vitro, but devoid of synergistic activity in microbiological assays. Here, via a multidisciplinary approach, including molecular modelling, synthesis, enzymology, microbiology, and X-ray crystallography, we optimized this series of compounds and identified low micromolar inhibitors active against clinically relevant MBLs (NDM-1- and VIM-type). The best inhibitors increased, to a certain extent, the susceptibility of NDM-1- and VIM-4-producing clinical isolates to meropenem. X-ray structures of three selected inhibitors in complex with NDM-1 elucidated molecular recognition at the base of potency improvement, confirmed in silico predicted orientation, and will guide further development steps.

PubMed: 38139809
DOI: 10.3390/ph16121682

Experimental method

X-RAY DIFFRACTION (1.78 Å)