6tma

VIM-2_1dj- Triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases

spinqualitylabelsall models 6tma, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tma is a 2 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.5Å Ligands: 9O8, CL, IOD, OH, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9K2N0_PSEAI Publication Abstract from PubMed Metallo-beta-lactamases (MBLs) are an emerging cause of bacterial antibiotic resistance by hydrolysing all classes of beta-lactams except monobactams, and the MBLs are not inhibited by clinically available serine-beta-lactamase inhibitors. Two of the most commonly encountered MBLs in clinical isolates worldwide - the New Delhi metallo-beta-lactamase (NDM-1) and the Verona integron-encoded metallo-beta-lactamase (VIM-2) - are included in this study. A series of several NH-1,2,3-triazoles was prepared by a three-step protocol utilizing Banert cascade reaction as the key step. The inhibitor properties were evaluated in biochemical assays against the MBLs VIM-2, NDM-1 and GIM-1, and VIM-2 showed IC50 values down to nanomolar range. High-resolution crystal structures of four inhibitors in complex with VIM-2 revealed hydrogen bonds from the triazole inhibitors to Arg228 and to the backbone of Ala231 or Asn233, along with hydrophobic interactions to Trp87, Phe61 and Tyr67. The inhibitors show reduced MIC in synergy assays with Pseudomonas aeruginosa and Escherichia coli strains harbouring VIM enzymes. The obtained results will be useful for further structural guided design of MBL inhibitors. Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases.,Muhammad Z, Skagseth S, Boomgaren M, Akhter S, Frohlich C, Ismael A, Christopeit T, Bayer A, Leiros HS Bioorg Med Chem. 2020 Aug 1;28(15):115598. doi: 10.1016/j.bmc.2020.115598. Epub, 2020 Jun 18. PMID:32631568 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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