8p1i

Single particle cryo-EM co-structure of Klebsiella pneumoniae AcrB with the BDM91288 efflux pump inhibitor at 2.97 Angstrom resolution

spinqualitylabelsall models 8p1i, resolution 2.97Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8p1i is a 3 chain structure with sequence from Klebsiella pneumoniae subsp. pneumoniae DSM 30104 = JCM 1662 = NBRC 14940. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.97Å Ligands: PG8, WQW, WR6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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