Summary

• Multidrug-resistance (MDR) efflux pumps are membrane transporter proteins that have a broad-spectrum of substrate specificity.
• Most classes of currently available antibiotics and compounds in development are considered to be 'Gram-positive only' and do not have clinical efficacy against Gram-negative bacteria.
• High intrinsic resistance results from the combination of efflux by MDR pumps and the low permeability of the outer membrane.
• MDR pumps from the resistance-nodulation-cell-division (RND) family are the main components of cellular defense against antibiotics; they have an unprecedented breadth of substrate promiscuity.
• The inner membrane RND in combination with the periplasmic 'adaptor' protein and the outer membrane channel extrude their substrates across the whole cellular envelope directly into the medium, a phenomenon referred to as trans-envelope transport.
• High-resolution structures have been determined for all the components of the tri-partite complex and provide the structural basis for understanding trans-envelope transport.
• RND transporters have a voluminous substrate-binding pocket that can accommodate a variety of substrates; this binding pocket is located in the large periplasmic domain of the pump.
• RND transporters function as trimers, with each monomer sequentially alternating through three phases of the efflux process: access, binding and extrusion.
• Elucidation of structure and transport mechanisms provides for multiple opportunities for the design of efflux pump inhibitors.
• Inhibition of efflux pumps in bacteria will significantly improve the effectiveness of antibacterial therapy.