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| - | ==VIM-1_1dh-Triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases== | + | ==VIM-2_1dh-Triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases== |
| | <StructureSection load='6tmc' size='340' side='right'caption='[[6tmc]], [[Resolution|resolution]] 1.40Å' scene=''> | | <StructureSection load='6tmc' size='340' side='right'caption='[[6tmc]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tmc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TMC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TMC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tmc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TMC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TMC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NL5:4-[2-(phenylsulfonyl)ethyl]-5-(propan-2-yloxymethyl)-1~{H}-1,2,3-triazole'>NL5</scene>, <scene name='pdbligand=OH:HYDROXIDE+ION'>OH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaVIM-2, bla vim-2, bla-VIM-2, blasVIM-2, blaVIM2, blm, VIM-2, vim-2, PAERUG_P32_London_17_VIM_2_10_11_06255 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NL5:4-[2-(phenylsulfonyl)ethyl]-5-(propan-2-yloxymethyl)-1~{H}-1,2,3-triazole'>NL5</scene>, <scene name='pdbligand=OH:HYDROXIDE+ION'>OH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tmc OCA], [http://pdbe.org/6tmc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tmc RCSB], [http://www.ebi.ac.uk/pdbsum/6tmc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tmc ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6tmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tmc OCA], [https://pdbe.org/6tmc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tmc RCSB], [https://www.ebi.ac.uk/pdbsum/6tmc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tmc ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q9K2N0_PSEAI Q9K2N0_PSEAI] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Christopeit, T]] | + | [[Category: Pseudomonas aeruginosa]] |
| - | [[Category: Leiros, H K.S]] | + | [[Category: Christopeit T]] |
| - | [[Category: Antibiotic]] | + | [[Category: Leiros H-KS]] |
| - | [[Category: Crystal structure]]
| + | |
| - | [[Category: Inhibition property]]
| + | |
| - | [[Category: Metallo-beta-lactamase inhibitor]]
| + | |
| - | [[Category: Nh-triazole]]
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| Structural highlights
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Muhammad Z, Skagseth S, Boomgaren M, Akhter S, Frohlich C, Ismael A, Christopeit T, Bayer A, Leiros HS. Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases. Bioorg Med Chem. 2020 Aug 1;28(15):115598. doi: 10.1016/j.bmc.2020.115598. Epub, 2020 Jun 18. PMID:32631568 doi:http://dx.doi.org/10.1016/j.bmc.2020.115598
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