A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene

Hendrik W. van Veen (), Richard Callaghan, Loredana Soceneantu, Alessandro Sardini, Wil N. Konings and Christopher F. Higgins
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Hendrik W. van Veen: Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen
Richard Callaghan: Imperial Cancer Research Fund Laboratories and Cancer Research Campaign Drug Resistance Group, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Loredana Soceneantu: Imperial Cancer Research Fund Laboratories and Cancer Research Campaign Drug Resistance Group, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford
Alessandro Sardini: King's College London
Wil N. Konings: Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen
Christopher F. Higgins: Imperial Cancer Research Fund Laboratories and Cancer Research Campaign Drug Resistance Group, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford

Nature, 1998, vol. 391, issue 6664, 291-295

Abstract: Abstract Bacteria have developed many fascinating antibiotic-resistance mechanisms1,2. A protein in Lactococcus lactis, LmrA, mediates antibiotic resistance by extruding amphiphilic compounds from the inner leaflet of the cytoplasmic membrane3,4. Unlike other known bacterial multidrug-resistance proteins, LmrA is an ATP-binding cassette (ABC) transporter5. The human multidrug-resistance P-glycoprotein6, 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 chemotherapy7,8. We expressed lmrA in human lung fibroblast cells. Surprisingly, LmrA was targeted to the plasma membrane and conferred typical multidrug resistance on these human cells. The pharmacological characteristics of LmrA and P-glycoprotein-expressing lung fibroblasts were very similar, and the affinities of both proteins for vinblastine and magnesium-ATP were indistinguishable. Blockers of P-glycoprotein-mediated multidrug resistance also inhibited LmrA-dependent drug resistance. Kinetic analysis of drug dissociation from LmrA expressed in plasma membranes of insect cells revealed the presence of two allosterically linked drug-binding sites indistinguishable from those of P-glycoprotein. These findings have implications for the reversal of antibiotic resistance in pathogenic microorganisms. Taken together, they demonstrate that bacterial LmrA and human P-glycoprotein are functionally interchangeable and that this type of multidrug-resistance efflux pump is conserved from bacteria to man.

Date: 1998
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DOI: 10.1038/34669

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