Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump

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 i...

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Autores principales:	Chih-Chia Su, Christopher E. Morgan, Sekhar Kambakam, Malligarjunan Rajavel, Harry Scott, Wei Huang, Corey C. Emerson, Derek J. Taylor, Phoebe L. Stewart, Robert A. Bonomo, Edward W. Yu
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Acinetobacter baumannii AdeB multidrug efflux pump membrane proteins multidrug efflux pump multidrug resistance cryo-EM Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1ff555a19acc43478d664ff88d6fb930
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spelling	oai:doaj.org-article:1ff555a19acc43478d664ff88d6fb9302021-11-15T16:22:08ZCryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump10.1128/mBio.01295-192150-7511https://doaj.org/article/1ff555a19acc43478d664ff88d6fb9302019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01295-19https://doaj.org/toc/2150-7511ABSTRACT 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.Chih-Chia SuChristopher E. MorganSekhar KambakamMalligarjunan RajavelHarry ScottWei HuangCorey C. EmersonDerek J. TaylorPhoebe L. StewartRobert A. BonomoEdward W. YuAmerican Society for MicrobiologyarticleAcinetobacter baumanniiAdeB multidrug efflux pumpmembrane proteinsmultidrug efflux pumpmultidrug resistancecryo-EMMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter baumannii AdeB multidrug efflux pump membrane proteins multidrug efflux pump multidrug resistance cryo-EM Microbiology QR1-502
spellingShingle	Acinetobacter baumannii AdeB multidrug efflux pump membrane proteins multidrug efflux pump multidrug resistance cryo-EM Microbiology QR1-502 Chih-Chia Su Christopher E. Morgan Sekhar Kambakam Malligarjunan Rajavel Harry Scott Wei Huang Corey C. Emerson Derek J. Taylor Phoebe L. Stewart Robert A. Bonomo Edward W. Yu Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump
description	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.
format	article
author	Chih-Chia Su Christopher E. Morgan Sekhar Kambakam Malligarjunan Rajavel Harry Scott Wei Huang Corey C. Emerson Derek J. Taylor Phoebe L. Stewart Robert A. Bonomo Edward W. Yu
author_facet	Chih-Chia Su Christopher E. Morgan Sekhar Kambakam Malligarjunan Rajavel Harry Scott Wei Huang Corey C. Emerson Derek J. Taylor Phoebe L. Stewart Robert A. Bonomo Edward W. Yu
author_sort	Chih-Chia Su
title	Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump
title_short	Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump
title_full	Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump
title_fullStr	Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump
title_full_unstemmed	Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump
title_sort	cryo-electron microscopy structure of an <named-content content-type="genus-species">acinetobacter baumannii</named-content> multidrug efflux pump
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/1ff555a19acc43478d664ff88d6fb930
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Cryo-Electron Microscopy Structure of an <named-content content-type="genus-species">Acinetobacter baumannii</named-content> Multidrug Efflux Pump

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