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MBio. 2019 Jul 2;10(4). pii: e01295-19. doi: 10.1128/mBio.01295-19.

Cryo-Electron Microscopy Structure of an Acinetobacter baumannii Multidrug Efflux Pump.

Author information

1
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
2
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.
3
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA edward.w.yu@case.edu.
#
Contributed equally

Abstract

Resistance-nodulation-cell division multidrug efflux pumps are membrane proteins that catalyze the export of drugs and toxic compounds out of bacterial cells. Within the hydrophobe-amphiphile subfamily, these multidrug-resistant proteins form trimeric efflux pumps. The drug efflux process is energized by the influx of protons. Here, we use single-particle cryo-electron microscopy to elucidate the structure of the Acinetobacter baumannii AdeB multidrug efflux pump embedded in lipidic nanodiscs to a resolution of 2.98 Å. We found that each AdeB molecule within the trimer preferentially takes the resting conformational state in the absence of substrates. We propose that proton influx and drug efflux are synchronized and coordinated within the transport cycle.IMPORTANCE Acinetobacter baumannii is a successful human pathogen which has emerged as one of the most problematic and highly antibiotic-resistant Gram-negative bacteria worldwide. Multidrug efflux is a major mechanism that A. baumannii uses to counteract the action of multiple classes of antibiotics, such as β-lactams, tetracyclines, fluoroquinolones, and aminoglycosides. Here, we report a cryo-electron microscopy (cryo-EM) structure of the prevalent A. baumannii AdeB multidrug efflux pump, which indicates a plausible pathway for multidrug extrusion. Overall, our data suggest a mechanism for energy coupling that powers up this membrane protein to export antibiotics from bacterial cells. Our studies will ultimately inform an era in structure-guided drug design to combat multidrug resistance in these Gram-negative pathogens.

KEYWORDS:

Acinetobacter baumannii ; AdeB multidrug efflux pump; cryo-EM; membrane proteins; multidrug efflux pump; multidrug resistance

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