Secondary multidrug transporters are integral membrane proteins that utilize the proton motive force to actively extrude antibiotics and other toxic compounds from cells. Such a simultaneous efflux of multiple drugs represents a major obstacle to successfully treating cancer and infectious diseases. However, in addition to their clinical importance, Mdr transporters also have intriguing mechanistic characteristics that differ substantially from those of substrate-specific transporters. Collectively, our studies of the E. coli Mdr transporter MdfA have demonstrated that in order for these transporters to mediate multidrug resistance, they must be exceptionally flexible in structure and function. Several fascinating examples will be presented.
