Structural Biology of Bacterial Multidrug Resistance Gene Regulators

Multidrug resistance (mdr)1 can be defined broadly as the ability of a cell to survive ordinarily lethal doses of more than one drug. Clearly, such resistance is a critical problem in the treatment of fungal and bacterial infections and cancer. Four general, but nonexclusive, mechanisms give rise to multidrug resistance: 1) detoxification by enzymatic modification or cleavage of drug; 2) genetic alteration of the intra- or extracellular targets; 3) decreased permeability of the cell membrane; and 4) active drug extrusion by multidrug transporters. Paramount to our understanding of mdr is the issue of recognition of structurally dissimilar substrates and how drug binding effects function. In bacteria many multidrug transporters are regulated directly (locally) by transcription factors, which also bind the substrates of these transporters, i.e. the drug can act as a transcriptional coactivator or inducer. Multiple mdr transporter genes are also regulated globally by activators such as MarA that do not necessarily bind drugs (1). The regulators are of keen interest because they are more amenable to structural studies than the membrane-bound transporters and thus offer a greater chance to obtain high resolution views of multidrug binding. Moreover, the local gene regulators are equally interesting as their DNA complexes directly reveal the mechanism of mdrtransporter gene regulation. This minireview will summarize the structures of known bacterial mdr regulators. Because our focus is more structural the reader is referred to one of several recent reviews that discuss the more biological aspects of global and local mdr regulation (2-5)