Mechanisms of multidrug transporters

FEMS Microbiology Reviews

Volumn 21, Issue 1, 1997, Pages 55-84

  Bolhuis, Henk ^a,b   Van Veen, Hendrik W ^a   Poolman, Bert ^a   Driessen, Arnold J M ^a   Konings, Wil N ^a  

^a UNIVERSITY OF GRONINGEN   (Netherlands)

^b MAX PLANCK INSTITUTE OF BIOCHEMISTRY   (Germany)

Author keywords

ABC transporters; Drug transport; Multidrug resistance; P glycoprotein

Indexed keywords

BACTERIAL PROTEIN; CARRIER PROTEIN;

ANTIBIOTIC RESISTANCE; BACTERIAL GENE; DRUG TRANSPORT; MULTIDRUG RESISTANCE; NONHUMAN; PROTEIN ANALYSIS; PROTEIN STRUCTURE; REVIEW;

AMINO ACID SEQUENCE; ATP-BINDING CASSETTE TRANSPORTERS; BIOLOGICAL TRANSPORT; CARRIER PROTEINS; DRUG RESISTANCE, MULTIPLE; HUMANS; MOLECULAR SEQUENCE DATA; P-GLYCOPROTEIN; STRUCTURE-ACTIVITY RELATIONSHIP;

BACTERIA (MICROORGANISMS); EUKARYOTA;

EID: 0030882820     PISSN: 01686445     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0168-6445(97)00051-X     Document Type: Review

References (205)

1. Cullinton, B.J. (1992) Drug-resistant TB may bring epidemic. Nature 356, 473.
2. Travis, J. (1994) Reviving the antibiotic miracle? Science 264, 360-362.
3. Lewis, K. (1994) Multidrug resistance pumps in bacteria: variations on a theme. Trends Biochem. Sci. 17, 18-21.
4. Nikaido, H. (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264, 382-388.
5. George, A.M. (1996) Multidrug resistance in enteric and other Gram-negative bacteria. FEMS Microbiol. Rev. 139, 1-10.
6. Borst, P. and Ouellette, M. (1995) New mechanisms of drug resistance in parasitic protozoa. Annu. Rev. Microbiol. 49, 427-460.
7. Bradley, G., Juranka, P.F. and Ling, V. (1988) Mechanism of multidrug resistance. Biochim. Biophys. Acta 948, 87-128.
8. Endicott, J.A. and Ling, V. (1989) The biochemistry of P-glycoprotein mediated multidrug resistance. Annu. Rev. Biochem. 58, 137-171.
9. Kaatz, G.W., Seo, S.M. and Ruble, C.A. (1993) Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 37, 1086-1094.
10. Yoshida, H., Bogaki, M., Nakamura, S., Ubukata, K. and Konno, M. (1990) Nucleotide sequence and characterization of the Staphylococcus aureus nor A gene, which confers resistance to quinolones. J. Bacteriol. 172, 6942-6949.
11. Tankovic, J., Desplaces, N., Duval, J. and Courvalin, P. (1994) In vivo selection during perfloxacin therapy of a mutant of Staphylococcus aureus with two mechanisms of fluoroquinolone resistance. Antimicrob. Agents Chemother. 38, 1149-1151.
12. Kern, W.V., Andriof, E., Oethinger, M., Kern, P., Hacker, J. and Marre, R. (1994) Emergence of fluoroquinolone-resistant Escherichia coli at a cancer center. Antimicrob. Agents Chemother. 38, 681-687.
13. Kornelisse, R.F., de Groot, R. and Neijens, H.J. (1995) Bacterial meningitis: Mechanisms of disease and therapy. Eur. J. Pediatr. 154, 85-96.
14. Guilfoile, P.G. and Hutchinson, C.R. (1991) A bacterial analog of the mdr gene of mammalian tumour cells is present in Streptomyces peuceticus, the producer of daunorubicin and doxorubicin. Proc. Natl. Acad. Sci. USA 88, 8553-8557.
15. Spratt, B.G. (1994) Resistance to antibiotics mediated by target alterations. Science 264, 388-393.
16. Rasmussen, B.A. and Bush, K. (1997) Carbapenem-hydrolyzing β-lactamases. Antimicrob. Agents Chemother. 41, 223-232.
17. Alton, N.K. and Vapnek, D. (1979) Nucleotide sequence analysis of the chloramphenicol resistance transposon Tn9. Nature 282, 864-869.
18. Chevereau, M., Daniels, P.J., Davies, J. and LeGoffic, F. (1974) Aminoglycoside resistance in bacteria mediated by gentamicin acetyltransferase II, an enzyme modifying the 2′-amino group of aminoglycoside antibiotics. Biochemistry 13, 598-603.
19. Takata, R., Osawa, S., Tanaka, K., Teraoka, H. and Tamaki, M. (1970) Genetic studies of the ribosomal proteins in Escherichia coli; Mapping of erythromycin resistance mutations which lead to alteration of a 50s ribosomal protein component. Mol. Gen. Genet. 109, 123-130.
20. Speer, B.S., Shoemaker, N.B. and Salyers, A.A. (1992) Bacterial resistance to tetracycline: Mechanism, transfer, and clinical significance. Clin. Microbiol. Rev. 5, 387-399.
21. Nikaido, H. and Thanassi, D.G. (1993) Penetration of lipophilic agents with multiple protonation sites into bacterial cells tetracyclines and fluoroquinolones as examples. Antimicrob. Agents Chemother. 37, 1393-1399.
22. Vaara, M. (1992) Agents that increase the permeability of the outer membrane. Microbiol. Rev. 56, 395-411.
23. Jarlier, V. and Nikaido, H. (1994) Mycobacterial cell wall: Structure and role in natural resistance to antibiotics. FEMS Microbiol. Lett. 123, 11-18.
24. Levy, S.B. (1992) Active efflux mechanisms for antimicrobial resistance. Antimicrob. Agents Chemother. 36, 695-703.
25. West, I.C. (1990) What determines the substrate specificity of the multidrug resistance pump. Trends Biochem. Sci. 15, 42-46.
26. Danø, K. (1973) Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochem. Biophys. Acta 323, 466-483.
27. Juliano, R.L. and Ling, V. (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455, 152-162.
28. Gottesman, M.M. and Pastan, I. (1988) The multidrug transporter, a double-edged sword. J. Biol. Chem. 263, 12163-12166.
29. Horio, M., Gottesman, M.M. and Pastan, I. (1988) ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc. Natl. Acad. Sci. USA 85, 3580-3584.
30. Schinkel, A.H. and Borst, P. (1991) Multidrug resistance mediated by P-glycoprotein. Cancer Biol. 2, 213-226.
31. Pedersen, P.L. (1995) Multidrug resistance: A fascinating, clinically relevant problem in bioenergetics. J. Bioenerg. Biomembr. 27, 3-5.
32. Shapiro, A.B. and Ling, V. (1995) Using purified P-glycoprotein to understand multidrug resistance. J. Bioenerg. Biomembr. 27, 7-13.
33. Shapiro, A.B. and Ling, V. (1995) Reconstitution of drug transport by purified P-glycoprotein. J. Biol. Chem. 270, 16167-16175.
34. Müller, M., Meijer, C., Zaman, G.J.R., Borst, P., Scheper, R.J., Mulder, N.H., de Vries, E.G. and Jansen, P.L.M. (1994) Overexpression of the gene encoding the multidrug resistance associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc. Natl. Acad. Sci. USA 91, 13033-13037.
35. Zaman, G.J.R., Flens, M.J., van Leusden, M.R., de Haas, M., Mulder, H.S., Lankelma, J., Pinedo, H.M., Scheper, R.J., Baas, F., Broxterman, H.J. and Borst, P. (1994) The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc. Natl. Acad. Sci. USA 91, 8822-8826.
36. Gründemann, D., Gorboulev, V., Gambaryan, S., Veyhl, M. and Koepsell, H. (1994) Drug extrusion mediated by a new prototype of polyspecific transporter. Nature 372, 549-552.
37. Zaman, G.J.R., Versantvoort, C.H.M., Smit, J.J.M., Eijdems, E.W.H.M., de Haas, M., Smith, A.J., Broxterman, H.J., Mulder, N.H., de Vries, E.G.E., Baas, F. and Borst, P. (1993) Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Res. 53, 1747-1750.
38. McMurry, L., Petrucci, R.E. and Levy, S.B. (1980) Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc. Natl. Acad. Sci. USA 77, 3974-3977.
39. Bissonnette, L., Champetier, S., Buisson, J.-P. and Roy, P.H. (1991) Characterization of the non-enzymatic chloramphenicol resistance (cmlA) gene of the In4 integron of Tn1696: similarity of the product to transmembrane transport proteins. J. Bacteriol. 173, 4493-4502.
40. Miyauchi, S., Komatsubara, M. and Kamo, N. (1992) In archaebacteria, there is a doxorubicin efflux pump similar to mammalian P-glycoprotein. Biochim. Biophys. Acta 1110, 144-150.
41. Bentley, J., Hyatt, L.S., Ainley, K., Parish, J.H., Herbert, R.B. and White, G.R. (1993) Cloning and sequence analysis of an Escherichia coli gene conferring bicyclomycin resistance. Gene 127, 117-120.
42. Bolhuis, H., Molenaar, D., Poelarends, G., van Veen, H.W., Poolman, B., Driessen, A.J.M. and Konings, W.N. (1994) Proton motive force-driven and ATP-dependent drug extrusion systems in multidrug resistant Lactococcus lactis. J. Bacteriol. 176, 6957-6964.
43. Silver, S. and Walderhaug, M. (1992) Gene regulation of plasmid- and chromosome-determined inorganic ion transport in bacteria. Microbiol. Rev. 56, 195-228.
44. Midgley, M. (1986) The phosphonium ion efflux system of Escherichia coli: relationship to the ethidium efflux system and energetic studies. J. Gen. Microbiol. 132, 3187-3193.
45. Tennent, J.M., Lyon, B.R., Midgley, M., Jones, I.G., Purewal, A.S. and Skurray, R.A. (1989) Physical and biochemical characterization of the qacA gene encoding antiseptic and disinfectant resistance in Staphylococcus aureus. J. Gen. Microbiol. 135, 1-10.
46. Neyfakh, A.A., Bidnenko, V.E. and Chen, L.B. (1991) Efflux-mediated multidrug resistance in Bacillus subtilis: similarities and dissimilarities with the mammalian system. Proc. Natl. Acad. Sci. USA 88, 4781-4785.
47. Lomovskaya, O. and Lewis, K. (1992) Emr, an Escherichia coli locus for multidrug resistance. Proc. Natl. Acad. Sci. USA 89, 8938-8942.
48. Hyde, S.C., Emsley, P., Hartshorn, M.J., Mimmack, M.M., Gileadi, U., Pearce, S.R., Gallagher, M.P., Gill, D.R., Hubbard, R.E. and Higgins, C.F. (1990) Structural model of the ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature 346, 362-365.
49. Ames, G.F.-L., Mimura, C.S. and Shyamala, V. (1990) Bacterial periplasmic permeases belong to a family of transport proteins operating from E. coli to human: traffic ATPases. FEMS Microbiol. Rev. 75, 429-446.
50. Higgins, C.F. (1992) ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8, 67-113.
51. Fath, M.J. and Kolter, R. (1993) ABC transporters: Bacterial exporters. Microbiol. Rev. 57, 995-1017.
52. Hughes, A.L. (1994) Evolution of the ATP-binding-cassette transmembrane transporters of vertebrates. Mol. Biol. Evol. 11, 899-910.
53. Barrasa, M.I., Tercero, J.A., Lacalle, R.A. and Jimenez, A. (1995) The ard1 gene from Streptomyces capreolus encodes a polypeptide of the ABC-transporters superfamily which confers resistance to the aminonucleoside antibiotic A201A. Eur. J. Biochem. 228, 562-569.
54. Linton, K.J. Cooper, H.N., Hunter, I.S. and Leadlay, P.F. (1994) An ABC-transporter from streptomyces longisporoflavus confers resistance to the polyether-ionophore antibiotic tetronasin. Mol. Microbiol. 11, 777-785.
55. Rodriguez, A.M., Olano, C., Vilches, C., Mendez, C. and Salas, J.A. (1993) Streptomyces antibioticus contains at least three oleandomycin-resistance determinants, one of which shows similarity with proteins of the ABC-transporter superfamily. Mol. Microbiol. 8, 571-582.
56. Olano, C., Rodríguez, A.M., Méndez, C. and Salas, J.A. (1995) A second ABC transporter is involved in oleandomycin resistance and its secretion by Streptomyces antibioticus. Mol. Microbiol. 16, 333-343.
57. Schoner, B., Geistlich, M., Rosteck, Jr., P. Rao, R.N., Reynolds, P., Cox, K., Burgett, S. and Hershberger, C. (1992) Sequence similarity between macrolide-resistance determinants and ATP-binding transport proteins. Gene 115, 93-96.
58. Garrido, M.C., Herrero, M., Kolter, R. and Moreno, F. (1988) The export of the DNA replication inhibitor microcin B17 provides immunity for the host cell. EMBO J. 7, 1853-1862.
59. Molenaar, D., Bolhuis, H., Abee, T., Poolman, B. and Konings, W.N. (1992) The efflux of a fluorescent probe is catalyzed by an ATP-driven extrusion system in Lactococcus lactis. J. Bacteriol. 174, 3118-3124.
60. Podlesek, Z., Comino, A., Herzog-Velikonja, B., Gur-Bertok, D., Komel, R. and Grabnar, M. (1995) Bacillus licheniformis bacitracin-resistance ABC transporter: relationship to mammalian multidrug resistance. Mol. Microbiol. 16, 969-976.
61. Noda, Y., Yoda, K., Takatsuki, A. and Yamasaki, M. (1992) TmrB protein, responsible for tunicamycin resistance of Bacillus subtilis, is a novel ATP-binding membrane protein. J. Bacteriol. 174, 4302-4307.
62. Van Veen, H.W., Venema, K., Bolhuis, H., Oussenko, I., Kok, J., Poolman, B., Driessen, A.J.M. and Konings, W.N. (1996b) Multidrug resistance mediated by a bacterial homolog of the human drug transporter MDR1. Proc. Natl. Acad. Sci. USA 93, 10668-10672.
63. Chen, C.-J., Chin, J.E., Ueda, K., Clark, D.P., Pastan, I., Gottesman, M.M. and Roninson, I.B. (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug resistant human cells. Cell 47, 381-389.
64. Higgins, C.F., Hiles, I.D., Salmond, G.P.C., Gill, D.R., Downie, J.A., Evans, I.J., Holland, I.B., Gray, L., Buckel, S.D., Bell, A.W. and Hermodson, M.A. (1986) A family of related ATP-binding subunits coupled to many distinct biological processes in bacteria. Nature 323, 448-450.
65. Mimura, C.S., Holbrook, S.R. and Ames, G.F.-L. (1991) Structural model of the nucleotide-binding conserved component of periplasmic permeases. Proc. Natl. Acad. Sci. USA 88, 84-88.
66. Gros, P., Croop, J. and Housman, D. (1986) Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47, 371-380.
67. Georges, E., Tsuruo, T. and Ling, V. (1993) Topology of P-glycoprotein as determined by epitope mapping of MRK-16 monoclonal antibody. J. Biol. Chem. 268, 1792-1798.
68. Schinkel, A.H., Kemp, S., Dollé, M., Rudenko, G. and Wagenaar, E. (1993) N-Glycosylation and deletion mutants of the human MDR1 P-glycoprotein. J. Biol. Chem. 268, 7474-7481.
69. Germann, U.A., Chambers, T.C., Ambudkar, S.V., Pastan, I. and Gottesman, M.M. (1995) Effects of phosphorylation of P-glycoprotein on multidrug resistance. J. Bioenerg. Biomembr. 27, 53-61.
70. Loo, T.W. and Clarke, D.M. (1995) Membrane topology of a cysteine-less mutant of human P-glycoprotein J. Biol. Chem. 270, 843-848.
71. Bibi, E. and Béjà, O. (1994) Membrane topology of multidrug resistance protein expressed in Escherichia coli; N-terminal domain. J. Biol. Chem. 269, 19910-19915.
72. Béjà, O. and Bibi, E. (1995) Multidrug resistance protein (Mdr)-alkaline phosphatase hybrids in Escherichia coli suggest a major revision in the topology of the C-terminal half of Mdr. J. Biol. Chem. 270, 12351-12354.
73. Zhang, J.-T., Lee, C.H., Duthie, M. and Ling, V. (1995) Topological determinants of internal transmembrane segments in P-glycoprotein sequences. J. Biol. Chem. 270, 1742-1746.
74. Zhang, J.-T. and Ling, V. (1991) Study of membrane orientation and glycosylated extracellular loops of mouse P-glycoprotein by in vitro translation. J. Biol. Chem. 266, 18224-18232.
75. Skach, W.R., Calayag, M.C. and Lingappa, V.R. (1993) Evidence for an alternate model of human P-glycoprotein structure and biogenesis. J. Biol. Chem. 268, 6903-6908.
76. Zhang, J.-T. and Ling, V. (1995) Involvement of cytoplasmic factors regulating the membrane orientation of P-glycoprotein sequences. Biochemistry 34, 9159-9165.
77. Blight, M.A. and Holland, I.B. (1990) Structure and function of haemolysin B, P-glycoprotein and other members of a novel family of ATP-dependent membrane translocators. Mol. Microbiol. 4, 873-880.
78. Hiles, I.D., Gallagher, M.P., Jamieson, D.J. and Higgins, C.F. (1987) Molecular characterization of the oligopeptide permease of Salmonella typhimurium. J. Mol. Biol. 195, 125-142.
79. Bissinger, P.H. and Kuchler, K. (1994) Molecular cloning and expression of the Saccharomyces cerevisiae STS1 gene product. A yeast ABC transporter conferring mycotoxin resistance. J. Biol. Chem. 269, 4180-4186.
80. Raymond, M., Gros, P., Whiteway, M. and Thomas, D.Y. (1992) Functional complementation of yeast ste6 by a mammalian multidrug resistance mdr gene. Science 256, 232-234.
81. Volkman, S.K., Cowman, A.F. and Wirth, D.F. (1995) Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 92, 8921-8925.
82. Bishop, L., Agbayani, R., Ambudkar, S.V., Maloney, P.C. and Ames, G.F.-L. (1989) Reconstitution of a bacterial periplasmic permease in proteoliposomes and demonstration of ATP hydrolysis concomitant with transport. Proc. Natl. Acad. Sci. USA 86, 6953-6957.
83. Sarkadi, B., Price, E.M., Boucher, R.C., Germann, U.A. and Scarborough, G.A. (1992) Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase. J. Biol. Chem. 267, 4854-4858.
84. Ambudkar, S.V., Lelong, I.H., Zhang, J., Cardarelli, C.O., Gottesman, M.M. and Pastan, I. (1992) Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulated ATP hydrolysis. Proc. Natl. Acad. Sci. USA 89, 8472-8476.
85. Senior, A.E., Al-Shawi, M.K. and Urbatsch, I.L. (1995) ATP hydrolysis by multidrug-resistance protein from chinese hamster ovary cells. J. Bioenerg. Biomembr. 27, 31-36.
86. Scarborough, G.A. (1995) Drug-stimulated ATPase activity of the human P-glycoprotein. J. Bioenerg. Biomembr. 27, 37-41.
87. Sharom, F.J. (1995) Characterization and functional reconstitution of the multidrug transporter. J. Bioenerg. Biomembr. 27, 15-22.
88. Ames, G.F.-L. and Joshi, A.K. (1990) Energy coupling in bacterial periplasmic permeases. J. Bacteriol. 172, 4133-4137.
89. Dean, D.A., Davidson, A.L. and Nikaido, H. (1989) Maltose transport in membrane vesicles of Escherichia coli is linked to ATP hydrolysis. Proc. Natl. Acad. Sci. USA 86, 9134-9138.
90. Loo, T.W. and Clarke, D.M. (1994) Mutations to amino acids located in predicted transmembrane segment 6 (TM6) modulate the activity and substrate specificity of human P-glycoprotein. Biochemistry 33, 14049-14057.
91. Urbatsch, I.L., Sankaran, B., Bhagat, S. and Senior, A.E. (1995) Both P-glycoprotein nucleotide-binding sites are catalytically active. J. Biol. Chem. 270, 26956-26961.
92. Allikmets, R., Gerrard, B., Court, D. and Dean, M. (1993) Cloning and organization of the abc and mdl genes of Escherichia coli: relationship to eukaryotic multidrug resistance. Gene 136, 231-236.
93. Karow, M. and Georgopoulos, C. (1993) The essential Escherichia coli msbA gene, a multicopy suppressor of null mutations in the htrB gene, is related to the universally conserved family of ATP-dependent translocators. Mol. Microbiol. 7, 69-79.
94. Ross, J.I., Eady, E.A., Cove, J.H. and Baumberg, S. (1995) Identification of a chromosomally encoded ABC-transport system with which the staphylococcal erythromycin exporter MsrA may interact. Gene 153, 93-98.
95. Beaudet, L. and Gros, P. (1995) Functional dissection of P-glycoprotein nucleotide-binding domains in chimeric and mutant proteins. J. Biol. Chem. 270, 17159-17170.
96. Raviv, Y., Pollard, H.B., Bruggemann, E.P., Pastan, I. and Gottesman, M.M. (1990) Photosensitized labeling of a functional multidrug transporter in living drug resistant tumor cells. J. Biol. Chem. 265, 3975-3980.
97. Bruggemann, E.P., Currier, S.J., Gottesman, M.M. and Pastan, I. (1992) Characterization of the azidopine and vinblastine binding site of P-glycoprotein. J. Biol. Chem. 267, 21020-21026.
98. Devine, S.E., Ling, V. and Melera, P.W. (1992) Amino acid substitutions in the sixth transmembrane domain of P-glycoprotein alter multidrug resistance. Proc. Natl. Acad. Sci. USA 89, 4564-4568.
99. Greenberger, L.M. (1993) Major photoaffinity drug labelling sites for Iodoaryl azidoprazosin in P-glycoprotein are within, or immediately C-terminal to, transmembrane domains 6 and 12. J. Biol. Chem. 268, 11417-11425.
100. Zhang, X.P., Collins, K.I. and Greenberger, L.M. (1995) Functional evidence that transmembrane 12 and the loop between transmembrane 11 and 12 form part of the drug-binding domain in P-glycoprotein encoded by MDR1. J. Biol. Chem. 270, 5441-5448.
101. Currier, S.J., Kane, S.E., Willingham, M.C., Cardarelli, C.O., Pastan, I. and Gottesman, M.M. (1992) Identification of residues in the first cytoplasmic loop of P-glycoprotein involved in the function of chimeric Human MDR1-MDR2 transporters. J. Biol. Chem. 267, 25153-25159.
102. Pawagi, A.B., Wang, J., Silverman, M., Reithmeier, R.A.F. and Deber, C.M. (1994) Transmembrane aromatic amino acid distribution in P-glycoprotein: A functional role in broad substrate specificity. J. Mol. Biol. 235, 554-564.
103. Dougherty, D.A. (1996) Cation-p interactions in chemistry and biology: A new view of benzene, Phe, Tyr, and Trp. Science 271, 163-168.
104. Yamaguchi, A., Udagawa, T. and Sawai, T. (1990) Transport of divalent cations with tetracycline as mediated by the transposon Tn10-encoded tetracycline resistance protein. J. Biol. Chem. 265, 4809-4813.
105. Bolhuis, H., Poelarends, G., van Veen, H.W., Poolman, B., Driessen, A.J.M. and Konings, W.N. (1995) The lactococcal lmrP gene encodes a proton motive force-dependent drug transporter. J. Biol. Chem. 270, 26092-26098.
106. Grinius, L.L. and Goldberg, E.B. (1994) Bacterial multidrug resistance is due to a single membrane protein which functions as a drug pump. J. Biol. Chem. 269, 29998-30004.
107. + and is soluble in organic solvents. J. Biol. Chem. 270, 6856-6863.
108. Marger, M.D. and Saier, Jr., M.H. (1993) A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport. Trends Biochem. Sci. 18, 13-20.
109. Saier, Jr., M.H., Tam, R., Reizer, A. and Reizer, J. (1994) Two novel families of bacterial membrane proteins concerned with nodulation, cell division and transport. Mol. Microbiol. 11, 841-847.
110. Paulsen, I.T. and Skurray, R.A. (1993) Topology, structure and evolution of two families of proteins involved in antibiotic and antiseptic resistance in eukaryotes and prokaryotes - an analysis. Gene 124, 1-11.
111. Paulsen, I.T. Brown, M.H., Dunstan, S.J. and Skurray, R.A. (1995) Molecular characterization of the staphylococcal multidrug resistance export protein QacC. J. Bacteriol. 177, 2827-2833.
112. Paulsen, I.T., Skurray, R.A., Tam, R., Saier, Jr., M.H., Turner, R.J., Weiner, J.H., Goldberg, E.B. and Grinius, L.L. (1996) The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs. Mol. Microbiol. 19, 1167-1175.
113. Paulsen, I.T., Brown, M.H. and Skurray, R.A. (1996) Proton-dependent multidrug efflux systems. Microbiol. Rev. 60, 575-608.
114. Takiff, H.E., Cimino, M., Musso, M.C., Weisbrod, T., Martinez, R., Delgado, M.B., Salazar, L., Bloom, B.R. and Jacobs, Jr., W.R. (1996) Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc. Natl. Acad. Sci. USA 93, 362-366.
115. Liu, J., Takiff, H.E. and Nikaido, H. (1996) Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. J. Bacteriol. 178, 3791-3795.
116. Schuldiner, S., Shirvan, A. and Linial, M. (1995). Vesicular Neurotransmitter transporters: from bacteria to humans. Physiol. Rev. 75, 369-392.
117. + toxicity encodes a vesicular amine transporter. Cell 70, 539-551.
118. Ahmed, M., Lyass, L., Markham, P.N., Taylor, S.S., Vazquez-Laslop, N. and Neyfakh, A.A. (1995) Two highly similar multidrug transporters of Bacillus subtilis whose expression is differentially regulated. J. Bacteriol. 177, 3904-3910.
119. von Heijne, G. (1986) The distribution of positively charged residues in bacterial inner membrane proteins correlates with the transmembrane topology. EMBO J. 5, 3021-3027.
120. + antiporter of Escherichia coli encoded by transposon Tn10; The structural resemblance and functional difference in the role of the duplicated sequence motif between hydrophobic segments 2 and 3 and segments 8 and 9. J. Biol. Chem. 268, 6496-6504.
121. Rouch, D.A., Cram, D.S., DiBerardino, D., Littlejohn, T.G. and Skurray, R.A. (1990) Efflux-mediated antiseptic resistance gene qacA from Staphylococcus aureus: common ancestry with tetracycline and sugar transport proteins. Mol. Microbiol. 4, 2051-2062.
122. + antiporter of Escherichia coli encoded by transposon TnIO; The role of a conserved sequence motif, GXXXYRXGRR, in a putative cytoplasmic loop between helices 2 and 3. J. Biol. Chem. 267, 19155-19162.
123. Jessen-Marshall, A.E., Paul, N.J. and Brooker, R.J. (1995) The conserved motif, GXXX(D/E)(R/K)XG[X](R/K)(R/K), in hydrophilic loop 2/3 of the lactose permease. J. Biol. Chem. 270, 16251-16257.
124. Paulsen, I.T., Brown, M.H., Littlejohn, T.G., Mitchell, B.A. and Skurray, R.A. (1996) Multidrug resistance proteins QacA and QacB from Staphylococcus aureus: Membrane topology and identification of residues involved in substrate specificity. Proc. Natl. Acad. Sci. USA 93, 3630-3635.
125. Furukawa, H., Tsay, J.T., Jackowski, S., Takamura, Y. and Rock, C.O. (1993) Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J. Bacteriol. 175, 3723-3729.
126. Dinh, T., Paulsen, I.T. and Saier, Jr., M.H. (1994) A family of extracytoplasmic proteins that allow transport of large molecules across the outer membranes of Gram-negative bacteria. J. Bacteriol. 176, 3825-3831.
127. Ma, D., Cook, D.N., Alberti, M., Pon, N.G., Nikaido, H. and Hearst, J.E. (1995) Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli. Mol. Microbiol. 16, 45-55.
128. Klein, J.R., Henrich, B.H. and Plapp, R. (1991) Molecular analysis and nucleotide sequence of the envCD operon of Escherichia coli. Mol. Gen. Genet. 230, 230-240.
129. Ma, D., Cook, D.N., Hearst, J.E. and Nikaido, H. (1994) Efflux pumps and drug resistance in Gram-negative bacteria. Trends Microbiol. 12, 489-493.
130. Poole, K., Krebes, K., McNally, C. and Neshat, S. (1993) Multiple antibiotic resistance in Pseudomonas aeruginosa -evidence for involvement of an efflux operon. J. Bacteriol. 175, 7363-7372.
131. Poole, K. (1994) Bacterial multidrug resistance - Emphasis on efflux mechanisms and Pseudomonas aeruginosa. J. Antimicrob. Chemother. 34, 453-456.
132. Köhler, T., Michéa-Hamzehpour, M., Henze, U., Gotoh, N., Kocjancic Curty, L. and Pechère, J.-C. (1997) Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa. Mol. Microbiol. 23, 345-354.
133. Poole, K., Gotoh, N, Tsujimoto, H., Zhao, Q.X., Wada, A., Yamasaki, T., Neshat, S., Yamagishi, J.-I., Li, X.-Z. and Nishino, T. (1996) Overexpression of the mexC-mexD-oprJ efflux operon in nfxB multidrug resistant strains of Pseudomonas aeruginosa. Mol. Microbiol. 21, 713-724.
134. Turner, R.J., Taylor, D.E. and Weiner, J.H. (1997) Expression of Escherichia coli TehA gives resistance to antiseptics and disinfectants similar to that conferred by multidrug resistance efflux pumps. Antimicrob. Agents Chemother. 41, 440-444.
135. Grinius, L.L., Dregunienne, G.. Goldberg, E.B., Liao, C.-H. and Projan, S.J. (1992) A staphylococcal multidrug resistance gene product is a member of a new protein family. Plasmid 27, 119-129.
136. Hillen, W. and Berens, C. (1994) Mechanisms underlying expression of Tn10 encoded tetracycline resistance. Annu. Rev. Microbiol. 48, 345-369.
137. 2+ reveals mechanism of antibiotic resistance. J. Mol. Biol. 247, 260-280.
138. Hinrichs, W., Kisker, C., Düvel, M., Müller, A., Tovar, K., Hillen, W. and Saenger, W. (1994) Structure of the Tet repressor-tetracycline complex and regulation of antibiotic resistance. Science 264, 418-420.
139. Lomovskaya, O., Lewis, K. and Matin, A. (1995) EmrR is a negative regulator of the Escherichia coli multidrug resistance pump EmrAB. J. Bacteriol. 177, 2328-2334.
140. Markham, P.N., Ahmed, M. and Neyfakh, A.A. (1996) The drug-binding activity of the multidrug responding transcriptional regulator BmrR resides in its C-terminal domain. J. Bacteriol. 178, 1473-1475.
141. Gambino, L., Gracheck, S.J. and Miller, P.F. (1993) Over-expression of the MarA positive regulator is sufficient to confer multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 175, 2888-2894.
142. Cohen, S.P., Hächler, H. and Levy, S.B. (1993) Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli. J. Bacteriol. 175, 1484-1492.
143. Zhanel, G.G., Karlowsky, J.A., Saunders, M.H., Davidson, R.J., Hoban, D.J., Hancock, R.E.W., Mclean, I. and Nicolle, L.E. (1995) Development of multiple-antibiotic-resistant (Mar) mutants of Pseudomonas aeruginosa after serial exposure to fluoroquinolones. Antimicrob. Agents Chemother. 39, 489-495.
144. Georges, E., Tsuruo, T. and Ling, V. (1993) Topology of P-glycoprotein as determined by epitope mapping of MRK-16 monoclonal antibody. J. Biol. Chem. 268, 1792-1798.
145. Ishida, H., Fuziwara, H., Kaibori, Y., Horiuchi, T., Sato, K. and Osada, Y. (1995) Cloning of multidrug resistance gene pqrA from Proteus vulgaris. Antimicrob. Agents Chemother. 39, 453-457.
146. Cohen, S.P., Levy, S.B., Foulds, J. and Rosner, J.L. (1993) Salicylate induction of antibiotic resistance in Escherichia coli; activation of the mar operon and a mar-independent pathway. J. Bacteriol. 175, 7856-7862.
147. Hächler, H., Cohen, S.P. and Levy, S.B. (1991) marA, a regulated locus which controls expression of chromosomal multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 173, 5532-5538.
148. Seoane, A.S. and Levy, S.B. (1995) Identification of new genes regulated by the marRAB operon in Escherichia coli. J. Bacteriol. 177, 530-535.
149. Seoane, A.S. and Levy, S.B. (1995) Characterization of MarR, the repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli. J. Bacteriol. 177, 3414-3419.
150. Martin, R.G. and Rosner, J.L. (1995) Binding of purified multiple antibiotic-resistance repressor protein (MarR) to mar operator sequences. Proc. Natl. Acad. Sci. USA 92, 5456-5460.
151. Rosner, J.L. and Slonczewski, J.L. (1994) Dual regulation of inaA by the multiple antibiotic resistance (Mar) and superoxide (SoxRS) stress response systems of Escherichia coli. J. Bacteriol. 176, 6262-6269.
152. Okusu, H., Ma, D. and Nikaido, H. (1996) AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J. Bacteriol. 178, 306-308.
153. Ariza, R.R., Cohen, S.P., Bachhawat, N., Levy, S.B. and Demple, B. (1994) Repressor mutations in the marRAB operon that activate oxidative stress genes and multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 176, 143-148.
154. Ahmed, M., Borsch, C.M., Taylor, S.S., Vazquez-Laslop, N. and Neyfakh, A.A. (1994) A protein that activates expression of a multidrug efflux transporter upon binding the transporter substrates. J. Biol. Chem. 269, 28506-28513.
155. Bolhuis, H., Molenaar, D., van Veen, H.W., Poolman, B., Driessen, A.J.M. and Konings, W.N. (1996) Multidrug resistance in Lactococcus lactis: evidence for ATP-dependent drug extrusion from the inner leaflet of the cytoplasmic membrane. EMBO J. 15, 4239-4245.
156. Bolhuis, H., van Veen, H.W., Brands, J.R., Putman, M., Poolman, B., Driessen, A.J.M. and Konings, W.N. (1996) Energetics and mechanism of drug transport mediated by the lactococcal MDR transporter LmrP. J. Biol. Chem. 271, 24123-24128.
157. Greenberger, L.M., Lisanti, C.J., Silva, J.T. and Horwitz, S.B. (1991) Domain mapping of the photoaffinity drug-binding sites in P-glycoprotein encoded by mouse mdr1b. J. Biol. Chem. 266, 20744-20751.
158. Urbatsch, I.L. and Senior, A.E. (1995) Effects of lipids on ATPase activity of purified chinese hamster P-glycoprotein. Arch. Biochem. Biophys. 316, 135-140.
159. Roepe, P.D. (1992) Analysis of the steady-state and initial rate of doxorubicin efflux from a series of multidrug-resistant cells expressing different levels of P-glycoprotein. Biochemistry 31, 12555-12564.
160. Wei, L.-Y. and Roepe, P.D. (1994) Low external pH and osmotic shock increase the expression of Human MDR protein. Biochemistry 33, 7229-7238.
161. Roepe, P.-D., Wei, L-Y., Hoffman, M.M. and Fritz, F. (1996) Altered drug translocation mediated by the MDR protein: Direct, indirect or both? J. Bioenerg. Biomembr. 28, 541-555.
162. Simon, S.M., Roy, D. and Schindler, M. (1994) Intracellular pH and the control of multidrug resistance. Proc. Natl. Acad. Sci. USA 91, 1128-1132.
163. Simon, S.M. and Schindler, M. (1994) Cell biological mechanisms of multidrug resistance in tumors. Proc. Natl. Acad. Sci. USA 91, 3497-3504.
164. Valverde, M.A., Diaz, M., Sepulveda, F., Gill, D.R., Hyde, S.C. and Higgins, C.F. (1992) Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 355, 830-833.
165. 3 exchange in Chinese hamster ovary cells. Biochemistry 33, 7239-7249.
166. Versantvoort, C.H.M., Broxterman, H.J., Feller, N., Dekker, H., Kuiper, C.M. and Lankelma, J. (1992) Probing daunorubicin accumulation defects in non-P-glycoprotein expressing multidrug resistant cell lines using digitonin. Int. J. Cancer 50, 906-911.
167. Altenberg, G.A., Young, G., Horton, J.K., Glass, D., Belli, J.A. and Reuss, L. (1993) Changes in intra- or extracellular pH do not mediate P-glycoprotein-dependent multidrug resistance. Proc. Natl. Acad. Sci. USA 90, 9735-9738.
168. Altenberg, G.A., Vanoye, C.G., Horton, J.K. and Reuss, L. (1994) Unidirectional fluxes of rhodamine 123 in multidrug resistant cells: Evidence against direct extrusion from the plasma membrane. Proc. Natl. Acad. Sci. USA 91, 4654-4657.
169. Schlemmer, S.R. and Sirotnak, F.M. (1994) Functional studies of P-glycoprotein in inside-out plasma membrane vesicles derived from murine erythroleukemia cells overexpressing MDR3: Properties and kinetics of the interaction of vinblastine with P-glycoprotein and evidence for its active mediated transport. J. Biol. Chem. 269, 31059-31066.
170. Ruetz, S. and Gros, P. (1994) Functional expression of P-glycoproteins in secretory vesicles. J. Biol. Chem. 269, 12277-12284.
171. Mülder, H.S., van Grondelle, R., Westerhoff, H.V. and Lankelma, J. (1993) A plasma membrane 'vacuum cleaner' for daunorubicin in non-P-glycoprotein multidrug resistant SW-1573 human non-small cell lung carcinoma cells: a study
172. De Wolf, F.A., Maliepaard, M., Van Dorsten, F., Berghuis, I., Nicolay, K. and de Kruijff, B. (1991) Comparable interaction of doxorubicin with various acidic phospholipids results in changes of lipid order and dynamics. Biochim. Biophys. Acta 1096, 67-80.
173. Speelmans, G., Staffhorst, R.W.H.M., de Kruijff, B. and de Wolf, F.A. (1994) Transport studies of doxorubicin in model membranes indicate a difference in passive diffusion across and binding at the outer and inner leaflets of the plasma membrane. Biochemistry 33, 13761-13768.
174. Speelmans, G., Staffhorst, R.W.H.M., de Wolf, F.A. and de Kruijff, B. (1995) Verapamil competes with doxorubicin for binding to anionic phospholipids resulting in increased internal concentrations and rates of passive transport of doxorubicin. Biochim. Biophys. Acta 1238, 137-146.
175. Gottesman, M.M. and Pastan, I. (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62, 385-427.
176. Higgins, C.F. and Gottesman, M.M. (1992) Is the multidrug transporter a flippase. Trends Biochem. Sci. 17, 18-21.
177. Higgins, C.F. (1994) Flip-Flop: The transmembrane translocation of lipids. Cell 79, 393-395.
178. Beck, W.T. and Qian, X.-D. (1992) Photoaffinity substrates for P-glycoprotein. Biochem. Pharmacol. 43, 89-93.
179. Wadler, S. and Yang, C.-P.H. (1991) Reversal of doxorubicin resistance by hydrophobic but not hydrophilic, forskolins. Mol. Pharmacol. 40, 960-964.
180. Homolya, L., Hollô, Z., Germann, U.A., Pastan, I., Gottesman, M.M. and Sarkadi, B. (1993) Fluorescent cellular indicators are extruded by the multidrug resistance protein. J. Biol. Chem. 268, 21493-21496.
181. Stein, W.D., Cardarelli, C., Pastan, I. and Gottesman, M.M. (1994) Kinetic evidence suggesting that the multidrug transporter differentially handles influx and efflux of its substrates. Mol. Pharmacol. 45, 763-772.
182. Takenouchi, T., Tabata, F., Iwata, Y., Hanzawa, H., Sugawara, M. and Ohya, S. (1996) Hydrophilicity of quinolones is not an exclusive factor for decreased activity in efflux-mediated resistant mutants of Staphylococcus aureus. Antimicrob. Agents Chemother. 40, 1835-1842.
183. Smit, J.J.M., Schinkel, A.H., Oude Elferink, R.P.J., Groen, A.K., Wagenaar, E., van Deemter, L., Mol, C.A.A.M., Ottenhoff, R., van der Lugt, N.M.T., van Roon, M.A., van der Valk, M.A., Offerhaus, G.J.A., Berns, A.J.M. and Borst, P. (1993) Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75, 451-462.
184. Ruetz, S. and Gros, P. (1994) Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Cell 77, 1071-1081.
185. Van Helvoort, A., Smith, A.J., Sprong, H., Fritzsche, I., Schinkel, A.H., Borst, P. and van Meer, G. (1996) MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 87, 507-517.
186. Wandersman, C. and Delepelaire, P. (1990) TolC, an Escherichia coli outer membrane protein required for haemolysin secretion. Proc. Natl. Acad. Sci. USA 87, 4776-4780.
187. Stanley, P., Koronakis, V. and Hughes, C. (1991) Mutational analysis supports a role for multiple structural features in the c-terminal secretion signal of Escherichia coli haemolysin. Mol. Microbiol. 5, 2391-2404.
188. Hughes, C., Stanley, P. and Koronakis, V. (1992) E coli haemolysin interactions with prokaryotic and eukaryotic cell membranes. BioEssays 14, 519-525.
189. Koronakis, V., Stanley, P., Koronakis, E. and Hughes, C. (1992) The HlyB/HlyD-dependent secretion of toxins by Gram-negative bacteria. FEMS Microbiol. Immunol. 105, 45-54.
190. Zhang, F., Yin, Y., Arrowsmith, C.H. and Ling, V. (1995) Secretion and circular dichroism analysis of the C-terminal signal peptides of HlyA and LktA. Biochemistry 34, 4193-4201.
191. Sheps, J.A., Cheung, I. and Ling, V. (1995) Hemolysin transport in Escherichia coli: Point mutants in HlyB compensate for a deletion in the predicted amphiphilic helix region of the HlyA signal. J. Biol. Chem. 270, 14829-14834.
192. Iwata, S., Ostermeier, C., Ludwig, B. and Michel, H. (1995) Structure at 2.8 Å resolution of cytochrome c oxidase from Paracoccus denitrificans. Nature 376, 660-669.
193. Sharma, R.C., Inoue, S., Roitelman, J., Schimke, R.T. and Simoni, R.D. (1992) Peptide transport by the multidrug resistance pump. J. Biol. Chem. 267, 5731-5734.
194. Eytan, G.D., Borgnia, M.J., Regev, R. and Assaraf, Y.G. (1994) Transport of polypeptide ionophores into proteoliposomes reconstituted with rat liver P-glycoprotein. J. Biol. Chem. 269, 26058-26065.
195. Kamimoto, Y., Gatmaitan, Z., Hsu, J. and Arias, I.M. (1989) The function of Gp170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. J. Biol. Chem. 264, 11693-11698.
196. Sikkema, J., de Bont, J.A.M. and Poolman, B. (1995) Mechanism of membrane toxicity of hydrocarbons. Microbiol. Rev. 59, 201-222.
197. Barabas, K., Sizensky, J.A. and Faulk, W.P. (1992) Transferrin conjugates of adriamycin are cytotoxic without intercalating nuclear DNA. J. Biol. Chem. 267, 9437-9442.
198. Devaux, P.F. (1992) Protein involvement in transmembrane lipid asymmetry. Annu. Rev. Biophys. Biomol. Struct. 21, 417-439.
199. Schachter, D., Cogan, U. and Abbott, R.E. (1982) Asymmetry of lipid dynamics in Human erythrocyte membranes studied with permeant fluorophores. Biochemistry 21, 2146-2150.
200. Devaux, P.F. and Zachowski, A. (1994) Maintenance and consequences of membrane phospholipid asymmetry. Chem. Phys. Lipids 73, 107-120.
201. Auland, M.E., Roufogalis, B.D., Devaux, P.F. and Zachowski, A. (1994) Reconstitution of ATP-dependent aminophospholipid translocation in proteoliposomes. Proc. Natl. Acad. Sci. USA 91, 10938-10942.
202. Ishikawa, T. (1992) The ATP-dependent glutathione S-conjugate export pump. Trends Biochem. Sci. 17, 463-468.
203. 4 and structurally related conjugates. J. Biol. Chem. 269, 27807-27810.
204. 4 and chemotherapeutic agents in membrane vesicles; Demonstration of glutathione-dependent vincristine transport. J. Biol. Chem. 271, 9675-9682.
205. Bibi, E., Gros, P. and Kaback, H.R. (1993) Functional expression of mouse mdr1 in Escherichia coli. Proc. Natl. Acad. Sci. USA 90, 9209-9213.