Multidrug efflux: Intriguing mechanistic concepts

The efflux of multiple drugs by Mdr transporters represents a major obstacle to successfully treating cancer and infectious diseases.

In addition to their clinical importance, Mdr transporters attracted us because they have intriguing mechanistic characteristics that differ substantially from those of substrate-specific transport systems.

Our studies of the E. coli Mdr transporter MdfA demonstrated that in order for these transporters to function in multidrug resistance, they must be exceptionally flexible in structure and function. As major goals for the future, we hope to elucidate critical structural and functional molecular details of multidrug efflux efflux through MdfA, by utilizing biochemical approaches, X-ray crystallography, and genetics.

 

Model for transport of long divalent cationic drugs in two successive transport cycles.

MdfA first binds and transports only one charged moiety (sphere) of the drug. Once the charged moiety is expelled, the transporter binds and transports the second half of the substrate. Two protons are imported per export of one drug molecule (Fluman et al, 2014).