Multidrug transporters in prokaryotic and eukaryotic cells: physiological functions and transport mechanisms

Multidrug transporters mediate the extrusion of structurally unrelated drug s from prokaryotic and eukaryotic cells. As a result of this efflux activit y, the cytoplasmic drug concentration in the cell is lowered to subtoxic le vels and, hence, cells become multidrug resistant. The activity of multidru g transporters interferes with the drug-based control of tumours and infect ious pathogenic microorganisms. There is an urgent need to understand the s tructure-function relationships in multidrug transporters that underlie the ir drug specificity and transport mechanism. Knowledge about the architectu re of drug and modulator binding sites and the link between energy-generati ng and drug translocating functions of multidrug transporters may allow one to rationally design new drugs that can poison or circumvent the activity of these transport proteins. Furthermore, if one is to inhibit multidrug tr ansporters in human cells, one should know more about their physiological s ubstrates and functions. This review will summarize important new insights into the role that multidrug transporters in general, and P-glycoprotein an d its bacterial homologue LmrA in particular, play in the physiology of the cell. In addition, the molecular basis of drug transport by these proteins will be discussed.