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Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors

Gaby Sennhauser1, Patrick Amstutz, Christophe Briand

  • 1University of Zurich, Zurich, Switzerland.

Plos Biology
|December 30, 2006
PubMed

Insights

The crystal structure of the multidrug exporter AcrB reveals distinct channels within its subunits, suggesting a novel drug export pathway. This finding advances understanding of how Escherichia coli achieves multidrug resistance.

Area of Science:

  • Structural Biology
  • Microbiology
  • Biochemistry

Background:

  • AcrB is a key component of the AcrAB-TolC efflux system in Escherichia coli, conferring resistance to numerous drugs.
  • Understanding the mechanism of AcrB is crucial for combating antimicrobial resistance.

Purpose of the Study:

  • To elucidate the structural basis of the multidrug exporter AcrB's function.
  • To investigate the drug transport pathway and proton motive force utilization.

Main Methods:

  • X-ray crystallography was used to determine the structure of trimeric AcrB.
  • A designed ankyrin-repeat protein (DARPin) inhibitor was used in complex with AcrB.

Main Results:

  • The crystal structure of AcrB in complex with a DARPin inhibitor was resolved at 2.5-A resolution.
  • The three AcrB subunits were observed in distinct conformations, revealing unique channels within each subunit.
  • Evidence suggests remote conformational coupling between channel access, exit, and proton translocation sites.

Conclusions:

  • The multidrug export pathway likely involves channels within individual AcrB subunits, not a central pore.
  • This structural insight provides a deeper understanding of the AcrB-mediated multidrug efflux mechanism.
  • The findings advance knowledge of how proton motive force drives drug export in bacteria.

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