8p1i
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Single particle cryo-EM co-structure of Klebsiella pneumoniae AcrB with the BDM91288 efflux pump inhibitor at 2.97 Angstrom resolution== | |
| + | <StructureSection load='8p1i' size='340' side='right'caption='[[8p1i]], [[Resolution|resolution]] 2.97Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8p1i]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae_subsp._pneumoniae_DSM_30104_=_JCM_1662_=_NBRC_14940 Klebsiella pneumoniae subsp. pneumoniae DSM 30104 = JCM 1662 = NBRC 14940]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8P1I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8P1I FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.97Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG8:1,2-DIOCTANOYL-SN-GLYCERO-3-[PHOSPHO-RAC-(1-GLYCEROL)'>PG8</scene>, <scene name='pdbligand=WQW:3-chloranyl-2,6-di(piperazin-4-ium-1-yl)quinoline'>WQW</scene>, <scene name='pdbligand=WR6:[(2~{R})-1-[[(2~{R})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-undecanoyloxy-propan-2-yl]+tricosanoate'>WR6</scene></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=8p1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8p1i OCA], [https://pdbe.org/8p1i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8p1i RCSB], [https://www.ebi.ac.uk/pdbsum/8p1i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8p1i ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Antimicrobial resistance is a global problem, rendering conventional treatments less effective and requiring innovative strategies to combat this growing threat. The tripartite AcrAB-TolC efflux pump is the dominant constitutive system by which Enterobacterales like Escherichia coli and Klebsiella pneumoniae extrude antibiotics. Here, we describe the medicinal chemistry development and drug-like properties of BDM91288, a pyridylpiperazine-based AcrB efflux pump inhibitor. In vitro evaluation of BDM91288 confirmed it to potentiate the activity of a panel of antibiotics against K. pneumoniae as well as revert clinically relevant antibiotic resistance mediated by acrAB-tolC overexpression. Using cryo-EM, BDM91288 binding to the transmembrane region of K. pneumoniae AcrB was confirmed, further validating the mechanism of action of this inhibitor. Finally, proof of concept studies demonstrated that oral administration of BDM91288 significantly potentiated the in vivo efficacy of levofloxacin treatment in a murine model of K. pneumoniae lung infection. | ||
| - | + | Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae.,Vieira Da Cruz A, Jimenez-Castellanos JC, Bornsen C, Van Maele L, Compagne N, Pradel E, Muller RT, Meurillon V, Soulard D, Piveteau C, Biela A, Dumont J, Leroux F, Deprez B, Willand N, Pos KM, Frangakis AS, Hartkoorn RC, Flipo M EMBO Mol Med. 2024 Jan;16(1):93-111. doi: 10.1038/s44321-023-00007-9. Epub 2023 , Dec 20. PMID:38177534<ref>PMID:38177534</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 8p1i" style="background-color:#fffaf0;"></div> |
| - | [[Category: Boernsen | + | == References == |
| - | [[Category: Frangakis | + | <references/> |
| - | [[Category: Pos | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Klebsiella pneumoniae subsp. pneumoniae DSM 30104 = JCM 1662 = NBRC 14940]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Boernsen C]] | ||
| + | [[Category: Frangakis AS]] | ||
| + | [[Category: Mueller RT]] | ||
| + | [[Category: Pos KM]] | ||
Current revision
Single particle cryo-EM co-structure of Klebsiella pneumoniae AcrB with the BDM91288 efflux pump inhibitor at 2.97 Angstrom resolution
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