PROTON-DEPENDENT MULTIDRUG EFFLUX SYSTEMS

Multidrug efflux systems display the ability to transport a variety of structurally unrelated drugs from a cell and consequently are capable of conferring resistance to a diverse range of chemotherapeutic agent s. This review examines multidrug efflux systems which use the proton motive force to drive drug transport. These proteins are likely to ope rate as multidrug/proton antiporters and have been identified in both prokaryotes and eukaryotes. Such proton-dependent multidrug efflux pro teins belong to three distinct families or superfamilies of transport proteins; the major facilitators superfamily (MFS), the small multidru g resistance (SMR) family, and the resistance/nodulation/cell division (RND) family. The MFS consists of symporters, antiporters, and within the MFS, three separate families include various multidrug/proton ant iport proteins. The SMR family consists of proteins with four TMS, and the multidrug efflux proteins within this family are the smallest kno wn secondary transporters. The RND family consists of 12-TMS transport proteins and includes a number of multidrug efflux systems require tw o auxiliary constituents, which might enable drug transport to occur a cross both members of the cell envelop. These auxiliary constituents b elong to the membrane fusion protein and the outer membrane factor fam ilies, respectively. This review examines in detail each of the charac terized proton-linked multidrug efflux systems. The molecular basis of the broad substrate specificity of these transporters is discussed. T he surprisingly wide Escherichia coli, for instance, possessing at lea st mine proton-dependent multidrug efflux systems with overlapping spe cificities, is examined. We also discuss whether the norma physiologic al role of the multidrug efflux systems is to protect the cell from to xic compounds of whether they fulfil primary functions unrelated to dr ug resistance and only efflux multiple drugs fortuitously or opportuni stically.