The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor.
The increasing number of pathogens expressing metallo-β-lactamases (MBLs), and in this way achieving resistance to β-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with β-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron-encoded metallo-β-lactamase 2 (VIM-2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of β-lactam-resistant infections. In this study, three triazolylthioacetamides were tested as inhibitors of VIM-2. One of the tested compounds showed clear inhibition of VIM-2, with an IC50of 20 µM. The crystal structure of the inhibitor in complex with VIM-2 was obtained by DMSO-free co-crystallization and was solved at a resolution of 1.50 Å. To our knowledge, this is the first structure of a triazolylthioacetamide inhibitor in complex with an MBL. Analysis of the structure shows that the inhibitor binds to the two zinc ions in the active site of VIM-2 and revealed detailed information on the interactions involved. Furthermore, the crystal structure showed that binding of the inhibitor induced a conformational change of the conserved residue Trp87.
The Norwegian Structural Biology Centre (Norstruct), Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
Tony
T
Christopeit
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, People's Republic of China.
Ke Wu
KW
Yang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710127, People's Republic of China.
Shao Kang
SK
Yang
The Norwegian Structural Biology Centre (Norstruct), Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
Hanna Kirsti S
HK
Leiros
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000201:enzymology; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D013853:Thioacetamide / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D065093:beta-Lactamase Inhibitors / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014230:Triazoles; D065093:beta-Lactamase Inhibitors; D013853:Thioacetamide; D014364:Tryptophan; C425108:beta-lactamase bla(vim-2); D001618:beta-Lactamases
DMSO-free co-crystallization; VIM-2; antibiotic resistance; carbapenemases; metallo-β-lactamases