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Microbial Multidrug Efflux: Introduction

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Microbial Multidrug Efflux: Introduction J. Mol. Microbiol. Biotechnol. (2001) 3(2): 143-144. MicrobialJMMB Multidrug Symposium Efflux 143 Microbial Multidrug Efflux: Introduction Ian T. Paulsen1*, and Kim Lewis2 to structural determination. The article by Alex Neyfakh presents this approach with the crystallographic analysis 1The Institute for Genomic Research, 9712 Medical of the purified ligand-binding domain of BmrR, the regulator Center Drive, Rockville, MD, 20850, USA of expression of the multidrug efflux transporter Bmr. BmrR 2Biotechnology Center, Department of Chemical and was shown to bind multiple hydrophobic substrates with Biological Engineering, Tufts University, 4 Colby Street, micromolar affinities through multiple electrostatic and Medford, MA 02155 hydrophobic interactions. The work on BmrR is the first important contribution to our understanding of the general principles of multidrug recognition. The phenomenon of multidrug efflux, whereby a single Another approach for examining the basis of drug transporter is capable of recognizing and transporting binding is to generate transporter mutants with alterations multiple drugs, with no apparent common structural in substrate specificity. Two examples of this are presented similarity, was first described in higher eukaryotes where in the articles by Bibi et al. and Brown and Skurray which P-glycoprotein was found to provide resistance to describe the mutagenesis and characterization of the anticancer chemotherapeutic agents via an ATP-driven multidrug efflux proteins MdfA of Escherichia coli and QacA efflux process. In the late 1980s and early 1990s, it became of Staphylococcus aureus, respectively. In each case, apparent that multidrug efflux systems were also present mutations have been isolated that affect the binding of only in microorganisms, with the identification of bacterial particular substrates and hence implicate particular multidrug transporters such as Bmr from Bacillus subtilis, residues in determining substrate specificity. Shimon QacA from Staphylococcus aureus and EmrB from Schuldiner’s group presents an extensive mutagenic Escherichia coli. Since that time, the number of analysis of the small multidrug efflux protein EmrE, using characterized multidrug efflux transporters has expanded cysteine-scanning mutagenesis. Approximately half of dramatically, and it appears from genomic analyses that amino acid residues in this transporter have been targeted multidrug efflux systems are probably essentially using this approach and biochemical characterization of ubiquitous. This symposium includes sixteen reviews that the mutants has identified residues involved in substrate together provide a comprehensive overview of the current binding. From these and mutagenic studies of other types status of research in the field of microbial multidrug efflux. of transporters it is becoming apparent that only a few Since the first studies on microbial multidrug efflux, residues in each transporter appear to directly interact with one focus of research and passionate debate has been on the transported substrate. how multidrug pumps function, i.e., what is the molecular Van Veen and colleagues have used Lactococcus mechanism of recognizing and transporting multiple lactis LmrA as a model for understanding the function of different drugs with dissimilar structures? This puzzle is ABC multidrug efflux pumps and have obtained evidence further compounded by the necessity for a transporter to that it may function by an alternating two-site mechanism discriminate between its substrate drugs and all cellular of transport. In this model, hydrolysis of ATP is coupled to compounds. drug efflux through the movement of an inward-facing high- One of the main barriers towards an understanding of affinity binding site with bound drug to an outward-facing the molecular mechanism of drug efflux systems in low-affinity binding site, from which the drug can dissociate. particular and membrane transporters in general is the lack Another interesting feature of LmrA, which it appears to of a high resolution structure for these proteins. Membrane share with a variety of other multidrug efflux systems, is proteins are notoriously difficult to purify and crystallize. that substrates can be extruded directly from the The article from Peter Henderson and collaborators phospholipid bilayer. presents an overview of the art of membrane transport Another related topic is how do drug efflux systems protein purification with details on the purification of composed of multiple protein constituents function? Nikaido multidrug, sugar and other transporters. In recent years and Zgurskaya have examined the molecular mechanism there have been high resolution structures determined for of the E. coli multicomponent AcrB-AcrA-TolC multidrug representatives of porins, electron transporters, channels efflux system, which is composed of an inner membrane and ion pumps, thus there has been a gradual transition drug efflux protein, AcrB; an accessory membrane fusion from structural membrane proteins to transporters for small protein, AcrA; and the TolC outer membrane channel. ligands and then towards larger ligands. While there are Crosslinking studies have suggested that AcrA and AcrB still no structures available for multidrug transporters or interact with each other, but that TolC may only be for transporters of other large solutes, at least this apparent transiently associated with the AcrAB complex. Evidence progression provides hope for the future. is accumulating that the role of AcrA is to bring the inner One approach around this problem is to examine the and outer membranes closer together. multidrug binding capabilities of proteins more amenable Another contentious question in the study of multidrug efflux pumps is: what is the native physiological role of drug efflux systems? Is it in detoxification? Or do multidrug *For correspondence. Email [email protected]; Tel. 1-301-8383531; efflux pumps have other physiologically relevant substrates Fax. 1-301-8380208. © 2001 Horizon Scientific Press Further Reading Caister Academic Press is a leading academic publisher of advanced texts in microbiology, molecular biology and medical research. 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