Structure and Function of Multidrug Transporters

Abstract

Toxic compounds have always been part of the natural environment in which microorganisms dwell. The development of strategies for life in this habitat has been crucial for survival of the cell. As a result, microorganisms have developed versatile mechanisms to resist antibiotics and other cytotoxic drugs. Examples are the enzymatic degradation or inactivation of drugs (Davies, 1994), and the alteration of drug targets (Spratt, 1994). In addition, microorganisms possess membrane proteins which catalyze transmembrane drug transport, and hence, are able to overcome cell cytotoxicity by lowering the cytoplasmic drug concentration (Lewis, 1994; Balzi and Goffeau, 1994; Borst and Ouellette, 1995). Some of these drug transporters are fairly specific for a given drug or class of drugs, but the so-called multidrug transporters have specificity for compounds with very different chemical structures and cellular targets. Microbial multidrug transporters can be amplified in drug resistant pathogenic microorganisms, and can shift their drug profiles, making them a menace to drug treatment. Multidrug transporters are also found in mammals, in which they are a cause of multidrug resistance of tumor cells. The structure and function of multidrug transporters is conserved from bacteria to man. On the basis of bioenergetic and structural criteria, multidrug transport systems can be divided into two major classes, Secondary transporters mediate the extrusion of drugs from the cell in a coupled exchange with ions (Paulsen et al, 1996a). ATP-binding cassette [ABC] transporters utilize the release of phosphate bond-energy by ATP hydrolysis, to pump drugs out of the cell (Higgins, 1992).