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INTRODUCTIONThe selection of drug-resistant pathogenicmicroorganisms in hospitalized patients with seriousinfections such as pneumonia, urinary tract infections,skin infections, and bacteremia has generally beenascribed to the widespread use of antimicrobial agents(1,2). Likewise, nutritive and therapeutic treatment offarm animals with antibiotics, amounting to half of theworld’s antibiotic output, has selected for drug resistantmicroorganisms that contaminate the food produced (3).Issues of concern regarding gram-negative bacteriainclude the extended drug resistance spectrum of β-lactamase-producing Escherichia coli, Salmonellatyphimurium and Klebsiella pneumonia. Currentconcerns with gram-positive pathogens are increasingmultidrug resistance in Listeria monocytogenes,methicillin-resistant Stalphylococcus aureusandpenicillin-resistant Streptococcus pneumonia (for review,see J. Kellner and D.E. Low in this issue of the MJM).Besides bacteria, parasitic protozoa are also responsiblefor some of the most devastating and prevalent diseasesof humans and domestic animals, such as malaria(Plasmodium spp.), (muco)cutaneous and visceralleishmaniasis (Leishmaniaspp.), African sleepingsickness (Trypanosoma brucei gambiense, Trypanosomabrucei rhodensiense), South-American Chagas’ disease(Trypanosoma cruzi), amoebic dysentery (Entamoebaspp.), and toxoplasmosis (Toxoplasma spp.) (for reviewsee (4)). Chemotherapeutic treatment of infections bythese parasites is being eroded by multidrug resistance.With few new drugs in the pipeline, prevention andcircumvention of microbial multidrug resistance aremedical and veterinary priorities, which require insightinto the molecular basis of microbial multidrugresistance.The presence of multidrug resistant pathogenic andnon-pathogenic microorganisms suggests thatmultidrug resistance did not arise recently in pathogensin response to antimicrobial chemotherapy. Toxiccompounds have always been part of the naturalenvironment in which microorganisms dwell. Thedevelopment of strategies for life in this habitat hasbeen crucial for survival of the cell. As a result,microorganisms can use various mechanisms to resistcytotoxic drugs. Microorganisms can eliminate the drugtarget in the cell through the alteration or replacement ofmolecules that are normally bound by the antibiotic (5).Alternatively, microorganisms can reduce theintracellular concentration of drugs by: (i) synthesizingenzymes that degrade antibiotics or that chemicallymodify, and so inactivate, the drugs (6), (ii) eliminatingentry ports for hydrophilic drugs, such as outermembrane porins in gram-negative bacteria (7), and (iii)manufacturing drug efflux systems that exportlipophilic drugs before these compounds have thechance to find their cellular targets (4,8,9). Some ofthese drug efflux systems are fairly specific for a givendrug or class of drugs, but the so-called multidrugtransporters have specificity for compounds with verydifferent chemical structures and cellular targets.Multidrug transporters can be amplified in drugresistant pathogenic microorganisms, and can shift theirdrug profiles, making them a menace to drug treatment.Multidrug transporters are also found in mammals, inwhich they are a cause of multidrug resistance of tumor |
