Most cells are protected by efflux pumps that actively expel toxic compounds. However, this evolutionarily conserved survival mechanism is also responsible for bacterial resistance to some antibiotics, and can greatly reduce the effectiveness of cytotoxic anticancer drugs. Efforts to combat these problems have been hampered by the fact that the structural basis of the interaction between efflux pumps and drugs has not been determined. This hurdle has now been overcome with the publication in Science of high-resolution X-ray crystallographic structures of complexes between the prototypical efflux pump Escherichia coli AcrB and four structurally diverse ligands.

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.