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Drug resistance

Pumping stations

Nature Reviews Drug Discovery volume 2, page 510 (2003)Cite this article

Energized by proton motive force, AcrB facilitates the efflux of a wide range of substrates, including most of the antibiotics used at present. It is a homotrimer of ∼110-kDa subunits, in which three periplasmic domains form a central 'funnel' and a connected pore. From the pore, three vestibules open into the periplasm, and three transmembrane domains form a large central cavity that extends into the cytoplasm.

Yu and colleagues have shown that four ligands — the dyes rhodamine and ethidium, the disinfectant dequalinium, and the antimicrobial ciprofloxacin — each use a different subset of amino-acid residues to bind at various positions within wild-type AcrB, a characteristic that greatly increases the range of potential drug–protein interactions. Complexes are stabilized by interactions between bound ligands, three of which bind simultaneously to the 5,000 Å3 central cavity, primarily by aromatic stacking, and through van der Waals and hydrophobic forces. Ligand binding also induces rotational movements in AcrB subunits that enlarge its periplasmic domain, possibly triggering the interaction between AcrB and the periplasmic protein AcrA that is essential to the efflux mechanism. These findings should facilitate the development of strategies to overcome drug resistance.

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References

ORIGINAL RESEARCH PAPER

  1. Yu, E. W. et al. Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 300, 976–980 (2003)

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FURTHER READING

  1. Coates, A. et al. The future challenges facing the development of new antimicrobial drugs. Nature Rev. Drug Disc. 1, 895–910 (2002)

    Article  CAS  Google Scholar 

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Authors
  1. Suzanne Farley
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Encyclopedia of Life Sciences

Bacterial antibiotic resistance

bacterial membrane transport: superfamilies of transport proteins

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Farley, S. Pumping stations. Nat Rev Drug Discov 2, 510 (2003). https://doi.org/10.1038/nrd1142

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