8P1I

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

Summary for 8P1I

• Entry DOI: 10.2210/pdb8p1i/pdb
• EMDB information: 17350
• Descriptor: Efflux pump membrane transporter, 3-chloranyl-2,6-di(piperazin-4-ium-1-yl)quinoline, [(2~{R})-1-[[(2~{R})-2,3-bis(oxidanyl)propoxy]-oxidanyl-phosphoryl]oxy-3-undecanoyloxy-propan-2-yl] tricosanoate, ... (4 entities in total)
• Functional Keywords: efflux pump inhibitor, transmembrane binding, antibiotic resistance, transport protein
• Biological source: Klebsiella pneumoniae subsp. pneumoniae DSM 30104 = JCM 1662 = NBRC 14940
• Total number of polymer chains: 3
• Total formula weight: 345549.79

Authors

Boernsen, C.,Mueller, R.T.,Pos, K.M.,Frangakis, A.S. (deposition date: 2023-05-12, release date: 2024-01-17, Last modification date: 2024-01-31)

Primary citation

Vieira Da Cruz, A.,Jimenez-Castellanos, J.C.,Bornsen, C.,Van Maele, L.,Compagne, N.,Pradel, E.,Muller, R.T.,Meurillon, V.,Soulard, D.,Piveteau, C.,Biela, A.,Dumont, J.,Leroux, F.,Deprez, B.,Willand, N.,Pos, K.M.,Frangakis, A.S.,Hartkoorn, R.C.,Flipo, M.
Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae.
Embo Mol Med, 16:93-111, 2024

PubMed 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 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.

PubMed: 38177534
DOI: 10.1038/s44321-023-00007-9

Experimental method

ELECTRON MICROSCOPY (2.97 Å)