In situ structure and assembly of the multidrug efflux pump AcrAB-TolC

Xiaodong Shi, Muyuan Chen, Zhili Yu, James M. Bell, Hans Wang, Isaac Forrester, Heather Villarreal, Joanita Jakana, Dijun Du, Ben F. Luisi, Steven J. Ludtke and Zhao Wang ()
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Xiaodong Shi: Baylor College of Medicine
Muyuan Chen: Baylor College of Medicine
Zhili Yu: Baylor College of Medicine
James M. Bell: Baylor College of Medicine
Hans Wang: Baylor College of Medicine
Isaac Forrester: CryoEM Core at Baylor College of Medicine
Heather Villarreal: CryoEM Core at Baylor College of Medicine
Joanita Jakana: CryoEM Core at Baylor College of Medicine
Dijun Du: University of Cambridge
Ben F. Luisi: University of Cambridge
Steven J. Ludtke: Baylor College of Medicine
Zhao Wang: Baylor College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-6

Abstract: Abstract Multidrug efflux pumps actively expel a wide range of toxic substrates from the cell and play a major role in intrinsic and acquired drug resistance. In Gram-negative bacteria, these pumps form tripartite assemblies that span the cell envelope. However, the in situ structure and assembly mechanism of multidrug efflux pumps remain unknown. Here we report the in situ structure of the Escherichia coli AcrAB-TolC multidrug efflux pump obtained by electron cryo-tomography and subtomogram averaging. The fully assembled efflux pump is observed in a closed state under conditions of antibiotic challenge and in an open state in the presence of AcrB inhibitor. We also observe intermediate AcrAB complexes without TolC and discover that AcrA contacts the peptidoglycan layer of the periplasm. Our data point to a sequential assembly process in living bacteria, beginning with formation of the AcrAB subcomplex and suggest domains to target with efflux pump inhibitors.

Date: 2019
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DOI: 10.1038/s41467-019-10512-6

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