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- EMDB-17350: Single particle cryo-EM co-structure of Klebsiella pneumoniae Acr... -
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Open data
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Basic information
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Title | 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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![]() | Efflux Pump Inhibitor / Transmembrane Binding / Antibiotic Resistance / TRANSPORT PROTEIN | |||||||||
Function / homology | : ![]() | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.97 Å | |||||||||
![]() | Boernsen C / Mueller RT / Pos KM / Frangakis AS | |||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae. Authors: Anais Vieira Da Cruz / Juan-Carlos Jiménez-Castellanos / Clara Börnsen / Laurye Van Maele / Nina Compagne / Elizabeth Pradel / Reinke T Müller / Virginie Meurillon / Daphnée Soulard / ...Authors: Anais Vieira Da Cruz / Juan-Carlos Jiménez-Castellanos / Clara Börnsen / Laurye Van Maele / Nina Compagne / Elizabeth Pradel / Reinke T Müller / Virginie Meurillon / Daphnée Soulard / Catherine Piveteau / Alexandre Biela / Julie Dumont / Florence Leroux / Benoit Deprez / Nicolas Willand / Klaas M Pos / Achilleas S Frangakis / Ruben C Hartkoorn / Marion Flipo / ![]() ![]() Abstract: 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 ...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. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 107.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19.5 KB 19.5 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 13.3 KB | Display | ![]() |
Images | ![]() | 92.8 KB | ||
Masks | ![]() | 209.3 MB | ![]() | |
Filedesc metadata | ![]() | 7 KB | ||
Others | ![]() ![]() | 194 MB 194 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 1.3 MB | Display | ![]() |
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Full document | ![]() | 1.3 MB | Display | |
Data in XML | ![]() | 21.6 KB | Display | |
Data in CIF | ![]() | 27.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8p1iMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Map
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Voxel size | X=Y=Z: 0.837 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Density Histograms |
-Half map: #2
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Projections & Slices |
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Density Histograms |
-Half map: #1
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Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Trimeric Klebsiella pneumoniae AcrB with BDM91288 efflux pump inh...
Entire | Name: Trimeric Klebsiella pneumoniae AcrB with BDM91288 efflux pump inhibitor |
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Components |
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-Supramolecule #1: Trimeric Klebsiella pneumoniae AcrB with BDM91288 efflux pump inh...
Supramolecule | Name: Trimeric Klebsiella pneumoniae AcrB with BDM91288 efflux pump inhibitor type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() Strain: FDAARGOS_775 |
-Macromolecule #1: Efflux pump membrane transporter
Macromolecule | Name: Efflux pump membrane transporter / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() Strain: FDAARGOS_775 |
Molecular weight | Theoretical: 114.489945 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MPNFFIDRPI FAWVIAIIIM LAGGLSILKL PVAQYPTIAP PAISITAMYP GADAETVQNT VTQVIEQNMN GIDHLMYMSS NGDSTGTAT ITLTFESGTD PDIAQVQVQN KLALATPLLP QEVQQQGISV EKASSSFLMV VGVINTNGTM NQDDISDYVA A NMKDPISR ...String: MPNFFIDRPI FAWVIAIIIM LAGGLSILKL PVAQYPTIAP PAISITAMYP GADAETVQNT VTQVIEQNMN GIDHLMYMSS NGDSTGTAT ITLTFESGTD PDIAQVQVQN KLALATPLLP QEVQQQGISV EKASSSFLMV VGVINTNGTM NQDDISDYVA A NMKDPISR TSGVGDVQLF GSQYAMRIWM DPNKLNNFQL TPVDVISALK AQNAQVAAGQ LGGTPPVKGQ QLNASIIAQT RL TNTEEFG NILLKVNQDG SQVRLRDVAK IELGGESYDV VAKFNGQPAS GLGIKLATGA NALDTANAIR AELAKMEPFF PSG MKIVYP YDTTPFVKIS IHEVVKTLVE AIILVFLVMY LFLQNFRATL IPTIAVPVVL LGTFAVLAAF GFSINTLTMF GMVL AIGLL VDDAIVVVEN VERVMAEEGL PPKEATRKSM GQIQGALVGI AMVLSAVFIP MAFFGGSTGA IYRQFSITIV SAMAL SVLV ALILTPALCA TMLKPIQKGS HGATTGFFGW FNRMFDKSTH HYTDSVGNIL RSTGRYLVLY LIIVVGMAWL FVRLPS SFL PDEDQGVFLS MAQLPAGATQ ERTQKVLDEM TNYYLTKEKD NVESVFAVNG FGFAGRGQNT GIAFVSLKDW SQRPGEE NK VEAITARAMG YFSQIKDAMV FAFNLPAIVE LGTATGFDFE LIDQGGLGHE KLTQARNQLF GMVAQHPDVL TGVRPNGL E DTPQFKIDID QEKAQALGVS ISDINTTLGA AWGGSYVNDF IDRGRVKKVY IMSEAKYRML PEDIGKWYVR GSDGQMVPF SAFSTSRWEY GSPRLERYNG LPSLEILGQA APGKSTGEAM ALMEELAGKL PSGIGYDWTG MSYQERLSGN QAPALYAISL IVVFLCLAA LYESWSIPFS VMLVVPLGVV GALLAATFRG LTNDVYFQVG LLTTIGLSAK NAILIVEFAK DLMEKEGKGL I EATLEAVR MRLRPILMTS LAFILGVMPL VISSGAGSGA QNAVGTGVMG GMVTATILAI FFVPVFFVVV RRRFSKKTED IE HSHQVEH HLEHHHHHH UniProtKB: UNIPROTKB: J2LW81 |
-Macromolecule #2: 3-chloranyl-2,6-di(piperazin-4-ium-1-yl)quinoline
Macromolecule | Name: 3-chloranyl-2,6-di(piperazin-4-ium-1-yl)quinoline / type: ligand / ID: 2 / Number of copies: 1 / Formula: WQW |
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Molecular weight | Theoretical: 333.859 Da |
Chemical component information | ![]() ChemComp-WQW: |
-Macromolecule #3: [(2~{R})-1-[[(2~{R})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphory...
Macromolecule | Name: [(2~{R})-1-[[(2~{R})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-undecanoyloxy-propan-2-yl] tricosanoate type: ligand / ID: 3 / Number of copies: 1 / Formula: WR6 |
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Molecular weight | Theoretical: 751.023 Da |
Chemical component information | ![]() ChemComp-WR6: |
-Macromolecule #4: 1,2-DIOCTANOYL-SN-GLYCERO-3-[PHOSPHO-RAC-(1-GLYCEROL)
Macromolecule | Name: 1,2-DIOCTANOYL-SN-GLYCERO-3-[PHOSPHO-RAC-(1-GLYCEROL) / type: ligand / ID: 4 / Number of copies: 2 / Formula: PG8 |
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Molecular weight | Theoretical: 497.537 Da |
Chemical component information | ![]() ChemComp-PG8: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 4.2 mg/mL | ||||||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 40 sec. / Pretreatment - Atmosphere: AIR | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Quantum SE / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 8487 / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Calibrated defocus max: 3.5 µm / Calibrated defocus min: 0.8 µm / Calibrated magnification: 130000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL |
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Output model | ![]() PDB-8p1i: |