A BACTERIAL ANTIBIOTIC-RESISTANCE GENE THAT COMPLEMENTS THE HUMAN MULTIDRUG-RESISTANCE P-GLYCOPROTEIN GENE

Bacteria have developed many fascinating antibiotic-resistance mechani sms(1,2). A protein in Lactococcus lactis, LmrA, mediates antibiotic r esistance by extruding amphiphilic compounds from the inner leaflet of the cytoplasmic membrane(3,4). Unlike other known bacterial multidrug -resistance proteins, LmrA is an ATP-binding cassette (ABC) transporte r(5). The human multidrug-resistance P-glycoprotein(6), encoded by the MDR1 gene, is also an ABC transporter, overexpression of which is one of the principal causes of resistance of human cancers to chemotherap y(7,8). We expressed ImrA in human lung fibroblast cells. Surprisingly , LmrA was targeted to the plasma membrane and conferred typical multi drug resistance on these human cells. The pharmacological characterist ics of LmrA and P-glycoprotein-expressing lung fibroblasts were very s imilar, and the affinities of both proteins for vinblastine and magnes ium-ATP were indistinguishable. Blockers of P-glycoprotein-mediated mu ltidrug resistance also inhibited LmrA-dependent drug resistance. Kine tic analysis of drug dissociation from LmrA expressed in plasma membra nes of insect cells revealed the presence of two allosterically linked drug-binding sites indistinguishable from those of P-glycoprotein. Th ese findings have implications for the reversal of antibiotic resistan ce in pathogenic microorganisms. Taken together, they demonstrate that bacterial LmrA and human P-glycopiotein are functionally interchangea ble and that this type of multidrug-resistance efflux pump is conserve d from bacteria to man.