9BFM

Cryo-EM co-structure of AcrB with the EPM35 efflux pump inhibitor

This is a non-PDB format compatible entry.

Summary for 9BFM

• Entry DOI: 10.2210/pdb9bfm/pdb
• EMDB information: 44500
• Descriptor: Multidrug efflux pump subunit AcrB, (2S)-1-(3,4-dichlorophenoxy)-3-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}piperidin-1-yl)propan-2-ol (3 entities in total)
• Functional Keywords: acrb multidrug efflux pump, translocase
• Biological source: Escherichia coli K-12
• Total number of polymer chains: 3
• Total formula weight: 341460.84

Authors

Su, C.C. (deposition date: 2024-04-18, release date: 2024-05-08)

Primary citation

Allgood, S.C.,Su, C.C.,Crooks, A.L.,Meyer, C.T.,Zhou, B.,Betterton, M.D.,Barbachyn, M.R.,Yu, E.W.,Detweiler, C.S.
Bacterial efflux pump modulators prevent bacterial growth in macrophages and under broth conditions that mimic the host environment.
mBio, 14:e0249223-, 2023

PubMed Abstract: Bacterial efflux pumps are critical for resistance to antibiotics and for virulence. We previously identified small molecules that inhibit efflux pumps (efflux pump modulators, EPMs) and prevent pathogen replication in host cells. Here, we used medicinal chemistry to increase the activity of the EPMs against pathogens in cells into the nanomolar range. We show by cryo-electron microscopy that these EPMs bind an efflux pump subunit. In broth culture, the EPMs increase the potency (activity), but not the efficacy (maximum effect), of antibiotics. We also found that bacterial exposure to the EPMs appear to enable the accumulation of a toxic metabolite that would otherwise be exported by efflux pumps. Thus, inhibitors of bacterial efflux pumps could interfere with infection not only by potentiating antibiotics, but also by allowing toxic waste products to accumulate within bacteria, providing an explanation for why efflux pumps are needed for virulence in the absence of antibiotics.

PubMed: 37921493
DOI: 10.1073/pnas.1901346116

Experimental method

ELECTRON MICROSCOPY (2.71 Å)