Structure of the AcrAB–TolC multidrug efflux pump

Abstract

The capacity of numerous bacterial species to tolerate antibiotics and other toxic compounds arises in part from the activity of energy-dependent transporters. In Gram-negative bacteria, many of these transporters form multicomponent ‘pumps’ that span both inner and outer membranes and are driven energetically by a primary or secondary transporter component1-7. A model system for such a pump is the acridine resistance complex of Escherichia coli1. This pump assembly comprises the outer-membrane channel TolC, the secondary transporter AcrB located in the inner membrane, and the periplasmic AcrA, which bridges these two integral membrane proteins. The AcrAB-TolC efflux pump is able to vectorially transport a diverse array of compounds with little chemical similarity, and accordingly confers resistance to a broad spectrum of antibiotics. Homologous complexes are found in many Gram-negative species, including pathogens of animals and plants. Crystal structures are available for the individual pump components2-7 and these have provided insights into substrate recognition, energy coupling and the transduction of conformational changes associated with the transport process. How the subunits are organised in the pump, their stoichiometry and the details of their interactions are not known and are under debate. In this manuscript, we present the pseudoatomic structure of a complete multidrug efflux pump in complex with a modulatory protein partner8. The model defines the quaternary organization of the pump, identifies key domain interactions, and suggests a cooperative process for channel assembly and opening. These findings illuminate the basis for drug resistance in numerous pathogenic bacterial species.

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“…However, it is also possible that hopanoids interact directly with certain proteins, modulating their action. There are diverse OM efflux proteins that interact with different types of transport systems to facilitate cellular efflux (52)(53)(54)(55). The activity of an OM efflux protein might potentially be impaired by altered diffusivity or defective gating associated with a change in membrane order (52).…”

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

“…109,110 Furthermore, recent efforts by Du et al have yielded a pseudoatomic structure of a fully assembled AcrAB-TolC MDR efflux pump, using a clever approach involving protein fusion. 111 The features summarized here stem from a wealth of recently reviewed structural data. 112,113 The RND pump typically exists as a trimer composed of a total of 12 transmembrane helices and two larger periplasmic loops.…”

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“…[78] Upon assembly the MFP connects the exit of the ABC transporter with the OMP opening and yields a "channel-tunnel" arrangement spanning the entire cell envelope. [79] The C-terminus of the cargo protein inserts into the conduit and initial transport is energized by Figure 3. Proposed mechanism for DNA secretion into host by type IV secretion system.…”