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Chapter 1 : Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms

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Abstract:

Four mechanisms have evolved to counteract tetracycline. They are active efflux (keeping tetracycline out of the cytoplasm), inactivation of the tetracycline molecule, rRNA mutations (preventing tetracycline from binding to the ribosome), and ribosomal protection (preventing tetracycline from binding to the ribosome). Most of the genes that exclusively encode tetracycline efflux are positioned on transferable plasmids and/or transposons. Minicells are formed by abberant cell division in certain mutants, contain only plasmid DNA, and synthesize only (radiolabelled) plasmid-encoded proteins. Two-dimensional (2D) crystallization was done with the Tet-6H fusion protein, which was over expressed in and purified as described, with a subsequent strong anion exchange chromatography step. Tet-6H was then reconstituted into a lipid bilayer to form protein arrays in two dimensions, which were negatively stained and examined by electron microscopy. Protection by tetracycline of (mutant) Cys residues from attack by N-ethylmaleimide (NEM) is another way of identifying the substrate binding site. Mutations of His257 in TM8 of TetA(B) permit downhill tetracycline transport in vesicles but no proton antiport, suggesting a role for this residue in proton exchange. Tetracycline resistance is inducible upon addition of a subinhibitory amount of tetracycline. The (K) and (L) genes are each inducible by tetracycline and are probably regulated by translation attenuation and translation reinitiation, respectively.

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Figure 1a

Multiple sequence alignment of the thirteen TetA proteins of group 1 by Clustal W. The shading was done using Multiple Align Show (http://www.cbio.psu.edu/sms/multi_align.html). Residues in vertical columns in which ≥70% of the residues are identical have black backgrounds; ≥70% similar residues have gray backgrounds. Similarity groups are (Gly), (Asp, Glu), (Arg, Lys), (Ala, Phe, Ile, Leu, Met, Pro, Val, Trp), and (Cys, His, Asn, Gln, Ser, Thr, Tyr). Transmembrane helices (TM) are shown as rectangles above the alignment. Black arrowheads show critical residues in TetA of class B, and a white arrow shows the position of Fenton cleavage in classes B and D. The start codon predicted in GenBank for class Z corresponds to a Val within TM1, so we have extended the translated sequence upstream 13 amino acids to be in step with its closest relative, class 33. For convenience we have moved the better-characterized class B and class C proteins from their true positions, just above classes D and G, respectively, to the top of the alignment. Gaps assigned by Clustal W ( ) in regions before TM1 and after TM12 have been eliminated. The GenBank accession numbers are B, P02980 (Bertrand sequence [70]); C, J01749; Z, AF121000; 33, AJ420072; A, X00006; G, S52437; Y, AF070999; D, X65876; 31, AJ250203; H, U00792; J, AF038993; E, L06940; 30, AF090987.1

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Image of Figure 1
Figure 1

Multiple sequence alignment of the thirteen TetA proteins of group 1 by Clustal W. The shading was done using Multiple Align Show (http://www.cbio.psu.edu/sms/multi_align.html). Residues in vertical columns in which ≥70% of the residues are identical have black backgrounds; ≥70% similar residues have gray backgrounds. Similarity groups are (Gly), (Asp, Glu), (Arg, Lys), (Ala, Phe, Ile, Leu, Met, Pro, Val, Trp), and (Cys, His, Asn, Gln, Ser, Thr, Tyr). Transmembrane helices (TM) are shown as rectangles above the alignment. Black arrowheads show critical residues in TetA of class B, and a white arrow shows the position of Fenton cleavage in classes B and D. The start codon predicted in GenBank for class Z corresponds to a Val within TM1, so we have extended the translated sequence upstream 13 amino acids to be in step with its closest relative, class 33. For convenience we have moved the better-characterized class B and class C proteins from their true positions, just above classes D and G, respectively, to the top of the alignment. Gaps assigned by Clustal W ( ) in regions before TM1 and after TM12 have been eliminated. The GenBank accession numbers are B, P02980 (Bertrand sequence [70]); C, J01749; Z, AF121000; 33, AJ420072; A, X00006; G, S52437; Y, AF070999; D, X65876; 31, AJ250203; H, U00792; J, AF038993; E, L06940; 30, AF090987.1

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Figure 2

The TetA(B) tetracycline/H antiporter. Transmembrane α-helices (TM) are indicated by gray rectangles numbered TM1-TM12. Circles indicate residues of class B possibly involved in substrate binding. The bracket indicates interdomain loop region corresponding to site in class A possibly involved in substrate binding. Squares indicate amino acids critical for tetracycline efflux. Triangles indicate amino acids possibly involved in local conformation change. The arrow indicates Fenton cleavage site. Scissors indicate the position where a truncation permits good activity. Horizontal lines indicate the permeability barrier for hydrophilic molecules. The circled star indicates the location in class C of its homologous Ser202. The other stars are placed at sites corresponding to those of class C and designate secondary suppressor mutations of the inactivating Ser202Phe substitution of class C.

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Figure 3

Projection map of 2D crystals of Tet-6H. The possible locations of the α and β halves of Tet-6H are superposed in two different trimer arrangements, each constrained to have α-α interactions. The page represents the plane of the membrane. Reprinted from Molecular Microbiology ( ) with permission of Blackwell Publishing.

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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References

/content/book/10.1128/9781555817572.chap1
1. Abramson, J.,, I. Smirnova,, V. Kasho,, G. Verner,, H. R. Kaback,, and S. Iwata. 2003. Structure and mechanism of the lactose permease of Escherichia coli. Science 301: 610 615.
2. Aldema, M. L.,, L. M. McMurry,, A. R. Walmsley,, and S. B. Levy. 1996. Purification of the Tn 10-specified tetracycline efflux antiporter TetA in a native state as a polyhistidine fusion protein. Mol. Microbiol. 19: 187 195.
3. Allard, J. D.,, and K. P. Bertrand. 1992. Membrane topology of the pBR322 tetracycline resistance protein: TetA-PhoA gene fusions and implications for the mechanism of TetA membrane insertion. J. Biol. Chem. 267: 17809 17819.
4. Bannam, T. L.,, P. A. Johanesen,, C. L. Salvado,, S. J. Pidot,, K. A. Farrow,, and J. I. Rood. 2004. The Clostridium perfringens TetA(P) efflux protein contains a functional variant of the Motif A region found in major facilitator superfamily transport proteins. Microbiology 150: 127 134.
5. Bertrand, K. P.,, K. Postle,, L. V. Wray, Jr., and W. S. Reznikoff. 1984. Construction of a single-copy promoter vector and its use in analysis of regulation of the transposon Tn 10 tetracycline resistance determinant. J. Bacteriol. 158: 910 919.
6. Brodersen, D. E.,, W. M. Clemons, Jr., A. P. Carter, R. J. Morgan-Warren, B. T. Wimberly, and V. Ramakrishnan. 2000. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103: 1143 1154.
7. Cheng, J.,, A. A. Guffanti,, and T. A. Krulwich. 1994. The chromosomal tetracycline resistance locus of Bacillus subtilis encodes a Na +/H + antiporter that is physiologically important at elevated pH. J. Biol. Chem. 269: 27365 27371.
8. Costello, M. J.,, J. Escaig,, K. Matsushita,, P. V. Viitanen,, D. R. Menick,, and H. R. Kaback. 1987. Purified lac permease and cytochrome o oxidase are functional as monomers. J. Biol. Chem. 262: 17072 17082.
9. Curiale, M.,, L. M. McMurry,, and S. B. Levy. 1984. Intracistronic complementation of the tetracycline resistance membrane protein specified by Tn 10. J. Bacteriol. 157: 211 217.
10. Curiale, M. S.,, and S. B. Levy. 1982. Two complementation groups mediate tetracycline resistance determined by Tn 10. J. Bacteriol. 151: 209 215.
11. De Rossi, E.,, M. C. Blokpoel,, R. Cantoni,, M. Branzoni,, G. Riccardi,, D. B. Young,, K. A. De Smet,, and O. Ciferri. 1998. Molecular cloning and functional analysis of a novel tetracycline resistance determinant, tet(V), from Mycobacterium smegmatis. Antimicrob. Agents Chemother. 42: 1931 1937.
12. Diaz-Torres, M. L.,, R. McNab,, D. A. Spratt,, A. Villedieu,, N. Hunt,, M. Wilson,, and P. Mullany. 2003. Novel tetracycline resistance determinant from the oral metagenome. Antimicrob. Agents Chemother. 47: 1430 1432.
13. Eckert, B.,, and C. F. Beck. 1989. Topology of the transposon Tn 10-encoded tetracycline resistance protein within the inner membrane of Escherichia coli. J. Biol. Chem. 264: 11663 11670.
14. Ermolova, N.,, L. Guan,, and H. R. Kaback. 2003. Intermolecular thiol cross-linking via loops in the lactose permease of Escherichia coli. Proc. Natl. Acad. Sci. USA 100: 10187 10192.
15. Fujihira, E.,, T. Kimura,, Y. Shiina,, and A. Yamaguchi. 1996. Transmembrane glutamic acid residues play essential roles in the metal-tetracycline/H + antiporter of Staphylococcus aureus. FEBS Lett. 391: 243 246.
16. Fujihira, E.,, T. Kimura,, and A. Yamaguchi. 1997. Roles of acidic residues in the hydrophilic loop regions of metaltetracycline/ H + antiporter Tet(K) of Staphylococcus aureus. FEBS Lett. 419: 211 214.
17. Fujihira, E.,, N. Tamura,, and A. Yamaguchi. 2002. Membrane topology of a multidrug efflux transporter, AcrB, in Escherichia coli. J. Biochem. (Tokyo) 131: 145 151.
18. Gerrits, M. M.,, M. Berning,, A. H. Van Vliet,, E. J. Kuipers,, and J. G. Kusters. 2003. Effects of 16S rRNA gene mutations on tetracycline resistance in Helicobacter pylori. Antimicrob. Agents Chemother. 47: 2984 2986.
19. Gerrits, M. M.,, M. R. de Zoete,, N. L. Arents,, E. J. Kuipers,, and J. G. Kusters. 2002. 16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori. Antimicrob. Agents Chemother. 46: 2996 3000.
20. Ginn, S. L.,, M. H. Brown,, and R. A. Skurray. 1997. Membrane topology of the metal-tetracycline/H + antiporter TetA (K) from Staphylococcus aureus. J. Bacteriol. 179: 3786 3789.
21. Griffith, J. K.,, T. Kogoma,, D. L. Corvo,, W. L. Anderson,, and A. L. Kazim. 1988. An N-terminal domain of the tetracycline resistance protein increases susceptibility to aminoglycosides and complements potassium uptake defects in Escherichia coli. J. Bacteriol. 170: 598 604.
22. Guay, G. G.,, M. Tuckman,, and D. M. Rothstein. 1994. Mutations in the tetA(B) gene that cause a change in substrate specificity of the tetracycline efflux pump. Antimicrob. Agents Chemother. 38: 857 860.
23. Guffanti, A. A.,, J. Cheng,, and T. A. Krulwich. 1998. Electrogenic antiport activities of the Gram-positive Tet proteins include a Na + (K +)/K + mode that mediates net K + uptake. J. Biol. Chem. 273: 26447 26454.
24. Guffanti, A. A.,, and T. A. Krulwich. 1995. Tetracycline/H + antiport and Na +/H + antiport catalyzed by the Bacillus subtilis TetA(L) transporter expressed in Escherichia coli. J. Bacteriol. 177: 4557 4561.
25. Guillaume, G.,, V. Ledent,, W. Moens,, and J. M. Collard. 2004. Phylogeny of efflux-mediated tetracycline resistance genes and related proteins revisited. Microb. Drug Resist. 10: 11 26.
26. Hansen, L. M.,, L. M. McMurry,, S. B. Levy,, and D. C. Hirsh. 1993. A new tetracycline resistance determinant, Tet H, from Pasteurella multocida specifying active efflux of tetracycline. Antimicrob. Agents Chemother. 37: 2699 2705.
27. Henderson, R.,, J. M. Baldwin,, K. H. Downing,, J. Lepault,, and F. Zemlin. 1986. Structure of purple membrane from Halobacterium halobium: recording, measurement and evaluation of electron micrographs at 3.5 angstroms resolution. Ultramicroscopy 19: 147 178.
28. Higgins, D.,, J. Thompson,, T. Gibson,, J. D. Thompson,, D. G. Higgins,, and T. J. Gibson. 1994. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22: 4673 4680.
29. Hinrichs, W.,, C. Kisker,, M. Duevel,, A. Mueller,, K. Tovar,, W. Hillen,, and W. Saenger. 1994. Structure of the Tet repressortetracycline complex and regulation of antibiotic resistance. Science 264: 418 420.
30.Reference deleted.
31. Huang, Y.,, M. J. Lemieux,, J. Song,, M. Auer,, and D. N. Wang. 2003. Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 301: 616 620.
32. Iwaki, S.,, N. Tamura,, T. Kimura-Someya,, S. Nada,, and A. Yamaguchi. 2000. Cysteine-scanning mutagenesis of transmembrane segments 4 and 5 of the Tn 10-encoded metal-tetracycline/ H + antiporter reveals a permeability barrier in the middle of a transmembrane water-filled channel. J. Biol. Chem. 275: 22704 22712.
33. Jewell, J. E.,, J. Orwick,, J. Liu,, and K. W. Miller. 1999. Functional importance and local environments of the cysteines in the tetracycline resistance protein encoded by plasmid pBR322. J. Bacteriol. 181: 1689 1693.
34. Jin, J.,, A. A. Guffanti,, D. H. Bechhofer,, and T. A. Krulwich. 2002. Tet(L) and Tet(K) tetracycline-divalent metal/H + antiporters: characterization of multiple catalytic modes and a mutagenesis approach to differences in their efflux substrate and coupling ion preferences. J. Bacteriol. 184: 4722 4732.
35. Jin, J.,, A. A. Guffanti,, C. Beck,, and T. A. Krulwich. 2001. Twelve-transmembrane-segment (TMS) version (DeltaTMS VII-VIII) of the 14-TMS Tet(L) antibiotic resistance protein retains monovalent cation transport modes but lacks tetracycline efflux capacity. J. Bacteriol. 183: 2667 2671.
36. Jin, J.,, and T. A. Krulwich. 2002. Site-directed mutagenesis studies of selected motif and charged residues and of cysteines of the multifunctional tetracycline efflux protein Tet(L). J. Bacteriol. 184: 1796 1800.
37. Kawabe, T.,, and A. Yamaguchi. 1999. Transmembrane remote conformational suppression of the Gly-332 mutation of the Tn 10-encoded metal-tetracycline/H + antiporter. FEBS Lett. 457: 169 173.
38. Kennan, R. M.,, L. M. McMurry,, S. B. Levy,, and J. I. Rood. 1997. Glutamate residues located within putative transmembrane helices are essential for TetA(P)-mediated tetracycline efflux. J. Bacteriol. 179: 7011 7015.
39. Khan, S. A.,, and R. P. Novick. 1983. Complete nucleotide sequence of pT181, a tetracycline-resistance plasmid from Staphylococcus aureus. Plasmid. 10: 251 259.
40. Kimura, T.,, M. Nakatani,, T. Kawabe,, and A. Yamaguchi. 1998. Roles of conserved arginine residues in the metal-tetracycline/ H + antiporter of Escherichia coli. Biochemistry 37: 5475 5480.
41. Kimura, T.,, T. Sawai,, and A. Yamaguchi. 1997. Remote conformational effects of the Gly-62 →Leu mutation of the Tn 10-encoded metal-tetracycline/H + antiporter of Escherichia coli and its second-site suppressor mutation. Biochemistry 36: 6941 6946.
42. Kimura, T.,, M. Suzuki,, T. Sawai,, and A. Yamaguchi. 1996. Determination of a transmembrane segment using cysteinescanning mutants of transposon Tn 10-encoded metaltetracycline/ H + antiporter. Biochemistry 35: 15896 15899.
43. Kimura-Someya, T.,, S. Iwaki,, S. Konishi,, N. Tamura,, Y. Kubo,, and A. Yamaguchi. 2000. Cysteine-scanning mutagenesis around transmembrane segments 1 and 11 and their flanking loop regions of Tn 10-encoded metal-tetracycline/H + antiporter. J. Biol. Chem. 275: 18692 18697.
44. Kubo, Y.,, S. Konishi,, T. Kawabe,, S. Nada,, and A. Yamaguchi. 2000. Proximity of periplasmic loops in the metaltetracycline/ H + antiporter of Escherichia coli observed on site-directed chemical cross-linking. J. Biol. Chem. 275: 5270 5274.
45. Levy, S. B.,, and L. McMurry. 1974. Detection of an inducible membrane protein associated with R-factor-mediated tetracycline resistance. Biochem. Biophys. Res. Comm. 56: 1060 1068.
46. Levy, S. B.,, and L. McMurry. 1978. Plasmid-determined tetracycline resistance involves new transport systems for tetracycline. Nature 276: 90 92.
47. Levy, S. B.,, and L. McMurry,. 1978. Probing the expression of plasmid-mediated tetracycline resistance in Escherichia coli, p. 177 180. In D. Schlessinger (ed.), Microbiology—1978. American Society for Microbiology, Washington, D.C.
48. Levy, S. B.,, L. M. McMurry,, T. M. Barbosa,, V. Burdett,, P. Courvalin,, W. Hillen,, M. C. Roberts,, J. I. Rood,, and D. E. Taylor. 1999. Nomenclature for new tetracycline resistance determinants. Antimicrob. Agents Chemother. 43: 1523 1524.
49. Lovett, P. S.,, and E. J. Rogers. 1996. Ribosome regulation by the nascent peptide. Microbiol. Rev. 60: 366 385.
50. Marshall, B.,, S. Morrissey,, P. Flynn,, and S. B. Levy. 1986. A new tetracycline-resistance determinant, class E, isolated from Enterobacteriaceae. Gene 50: 111 117.
51. Mazurkiewicz, P.,, G. J. Poelarends,, A. J. Driessen,, and W. N. Konings. 2004. Facilitated drug influx by an energy-uncoupled secondary multidrug transporter. J. Biol. Chem. 279: 103 108.
52. McMurry, L. M.,, M. L. Aldema-Ramos,, and S. B. Levy. 2002. Fe 2+-tetracycline-mediated cleavage of the Tn 10 tetracycline efflux protein TetA reveals a substrate binding site near glutamine 225 in transmembrane helix 7. J. Bacteriol. 184: 5113 5120.
53. McMurry, L. M.,, M. Hendricks,, and S. B. Levy. 1986. Effects of toluene permeabilization and cell deenergization on tetracycline resistance in Escherichia coli. Antimicrob. Agents Chemother. 29: 681 686.
54. McMurry, L. M.,, and S. B. Levy. 1995. The NH 2-terminal half of the tetracycline efflux protein from Tn 10 contains a functional dimerization domain. J. Biol. Chem. 270: 22752 22757.
55. McMurry, L. M.,, and S. B. Levy. 1998. Revised sequence of OtrB (Tet347) tetracycline efflux protein from Streptomyces rimosus. Antimicrob. Agents Chemother. 42: 3050.
56. McMurry, L. M.,, and S. B. Levy,. Tetracycline resistance determinants in gram-positive bacteria. In V. A. Fischetti,, R. P. Novick,, J. J. Ferretti,, D. A. Portnoy,, and J. I. Rood (ed.), Gram-Positive Pathogens, 2nd ed., in press. ASM Press, Washington, D.C.
57. McMurry, L. M.,, and S. B. Levy,. 2000. Tetracycline resistance in Gram-positive bacteria, p. 660 677. In V. A. Fischetti,, R. P. Novick,, J. J. Ferretti,, D. A. Portnoy,, and J. I. Rood (ed.), Gram-Positive Pathogens. ASM Press, Washington, D.C.
58. McMurry, L. M.,, B. H. Park,, V. Burdett,, and S. B. Levy. 1987. Energy-dependent efflux mediated by class L ( tetL) tetracycline resistance determinant from streptococci. Antimicrob. Agents Chemother. 31: 1648 1650.
59. McMurry, L. M.,, R. E. Petrucci, Jr., and S. B. Levy. 1980. Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc. Natl. Acad. Sci. USA 77: 3974 3977.
60. McMurry, L. M.,, M. Stephan,, and S. B. Levy. 1992. Decreased function of the class B tetracycline efflux protein Tet with mutations at aspartate 15, a putative intramembrane residue. J. Bacteriol. 174: 6294 6297.
61. McNicholas, P.,, I. Chopra,, and D. M. Rothstein. 1992. Genetic analysis of the tetA(C) gene on plasmid pBR322. J. Bacteriol. 174: 7926 7933.
62. McNicholas, P.,, M. McGlynn,, G. G. Guay,, and D. M. Rothstein. 1995. Genetic analysis suggests functional interactions between the N- and C-terminal domains of the TetA(C) efflux pump encoded by pBR322. J. Bacteriol. 177: 5355 5357.
63. Mendez, B.,, C. Tachibana,, and S. B. Levy. 1980. Heterogeneity of tetracycline resistance determinants. Plasmid 3: 99 108.
64. Meyers, E.,, and D. A. Smith. 1962. Microbiological degradation of tetracyclines. J. Bacteriol. 84: 797 802.
65. Miller, K. W.,, P. L. Konen,, J. Olsen,, and K. M. Ratanavanich. 1993. Membrane protein topology determination by proteolysis of maltose binding protein fusions. Anal. Biochem. 215: 118 128.
66. Mojumdar, M.,, and S. A. Khan. 1988. Characterization of the tetracycline resistance gene of plasmid pT181 of Staphylococcus aureus. J. Bacteriol. 170: 5522 5528.
67. Murakami, S.,, R. Nakashima,, E. Yamashita,, and A. Yamaguchi. 2002. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419: 587 593.
68. Nakamura, A.,, M. Nakagawa,, H. Yoshikoshi,, S. Shoutou,, K. O’Hara,, and T. Sawai. 2002. Novel enzymatically determined minocycline-resistance in a Pseudomonas aeruginosa clinical isolate, abstr. C1-1603. In Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology.
69. Nelson, M. L.,, B. H. Park,, and S. B. Levy. 1994. Molecular requirements for the inhibition of the tetracycline antiport protein and the effect of potent inhibitors on the growth of tetracycline-resistant bacteria. J. Med. Chem. 37: 1355 1361.
70. Nguyen, T. T.,, K. Postle,, and K. P. Bertrand. 1983. Sequence homology between the tetracycline-resistance determinants of Tn 10 and pBR322. Gene 25: 83 92.
71. Nikaido, H. 1998. Multiple antibiotic resistance and efflux. Curr. Opin. Microbiol. 1: 516 523.
72. Nonaka, L.,, and S. Suzuki. 2002. New Mg 2+-dependent oxytetracycline resistance determinant tet 34 in Vibrio isolates from marine fish intestinal contents. Antimicrob. Agents Chemother. 46: 1550 1552.
73. Orth, P.,, D. Schnappinger,, W. Hillen,, W. Saenger,, and W. Hinrichs. 2000. Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system. Nat. Struct. Biol. 7: 215 219.
74. Park, B. H.,, and S. B. Levy. 1988. The cryptic tetracycline resistance determinant on Tn 4400 mediates tetracycline degradation as well as tetracycline efflux. Antimicrob. Agents Chemother. 32: 1797 1800.
75. Paulsen, I. T.,, M. H. Brown,, and R. A. Skurray. 1996. Proton-dependent multidrug efflux systems. Microbiol. Rev. 60: 575 608.
76. Pioletti, M.,, F. Schlunzen,, J. Harms,, R. Zarivach,, M. Gluhmann,, H. Avila,, A. Bashan,, H. Bartels,, T. Auerbach,, C. Jacobi,, T. Hartsch,, A. Yonath,, and F. Franceschi. 2001. Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J. 20: 1829 1839.
77. Ridenhour, M. B.,, H. M. Fletcher,, J. E. Mortensen,, and L. Daneo-Moore. 1996. A novel tetracycline-resistant determinant, tet(U), is encoded on the plasmid pKQ10 in Enterococcus faecium. Plasmid 35: 71 80.
78. Roberts, M. C., 1997. Genetic mobility and distribution of tetracycline resistance determinants, p. 206 218. In D. J. Chadwick (ed.), Antibiotic Resistance: Origins, Evolution, Selection, and Spread. John Wiley and Sons, Chichester, U.K.
79. Roberts, M. C. 2004. Personal communication.
80. Roberts, M. C. 1996. Tetracycline resistance determinants: mechanisms of action, regulation of expression, genetic mobility, and distribution. FEMS Microbiol. Rev. 19: 1 24.
81. Rosen, B. P.,, and T. Tsuchiya. 1979. Preparation of everted membrane vesicles from Escherichia coli for the measurement of calcium transport. Methods Enzymol. 56: 233 241.
82. Ross, J. I.,, E. A. Eady,, J. H. Cove,, and W. J. Cunliffe. 1998. 16S rRNA mutation associated with tetracycline resistance in a gram-positive bacterium. Antimicrob. Agents Chemother. 42: 1702 1705.
83. Rubin, R. A.,, and S. B. Levy. 1990. Interdomain hybrid tetracycline proteins confer tetracycline resistance only when they are derived from closely related members of the tet gene family. J. Bacteriol. 172: 2303 2312.
84. Rubin, R. A.,, and S. B. Levy. 1991. Tet protein domains interact productively to mediate tetracycline resistance when present on separate polypeptides. J. Bacteriol. 173: 4503 4509.
85. Rubin, R. A.,, S. B. Levy,, R. L. Heinrikson,, and F. J. Kézdy. 1990. Gene duplication in the evolution of the two complementing domains of Gram-negative bacterial tetracycline efflux proteins. Gene 87: 7 13.
86. Safferling, M.,, H. Griffith,, J. Jin,, J. Sharp,, M. De Jesus,, C. Ng,, T. A. Krulwich,, and D. N. Wang. 2003. TetL tetracycline efflux protein from Bacillus subtilis is a dimer in the membrane and in detergent solution. Biochemistry 42: 13969 13976.
87. Sapunaric, F. M.,, and S. B. Levy. 2003. Second-site suppressor mutations for the serine 202 to phenylalanine substitution within the interdomain loop of the tetracycline efflux protein Tet(C). J. Biol. Chem. 278: 28588 28592.
87a.. Sapunaric, F. M.,, and S. B. Levy. Substitutions in the interdomain loop of the Tn 10 TetA efflux transporter alter tetracycline resistance and substrate specificity. Microbiology, in press.
88. Saraceni-Richards, C. A.,, and S. B. Levy. 2000. Evidence for interactions between helices 5 and 8 and a role for the interdomain loop in tetracycline resistance mediated by hybrid Tet proteins. J. Biol. Chem. 275: 6101 6106.
89. Saraceni-Richards, C. A.,, and S. B. Levy. 2000. Second-site suppressor mutations of inactivating substitutions at Gly247 of the tetracycline efflux protein, Tet(B). J. Bacteriol. 182: 6514 6516.
90. Sato, K.,, M. H. Sato,, A. Yamaguchi,, and M. Yoshida. 1994. Tetracycline/H + antiporter was degraded rapidly in Escherichia coli cells when truncated at last transmembrane helix and this degradation was protected by overproduced GroEL/ES. Biochem. Biophys. Res. Commun. 202: 258 264.
91. Schnappinger, D.,, and W. Hillen. 1996. Tetracyclines: antibiotic action, uptake, and resistance mechanisms. Arch. Microbiol. 165: 359 369.
92. Sloan, J.,, L. M. McMurry,, D. Lyras,, S. B. Levy,, and J. I. Rood. 1994. The Clostridium perfringens Tet P determinant comprises two overlapping genes: tetA(P), which mediates active tetracycline efflux, and tetB(P), which is related to the ribosomal protection family of tetracycline-resistance determinants. Mol. Microbiol. 11: 403 415.
93. Someya, Y.,, T. Kimura-Someya,, and A. Yamaguchi. 2000. Role of the charge interaction between Arg(70) and Asp(120) in the Tn 10-encoded metal-tetracycline/H + antiporter of Escherichia coli. J. Biol. Chem. 275: 210 214.
94. Someya, Y.,, A. Niwa,, T. Sawai,, and A. Yamaguchi. 1995. Site-specificity of the second-site suppressor mutation of the Asp-285 →Asn mutant of metal-tetracycline/H + antiporter of Escherichia coli and the effects of amino acid substitutions at the first and second sites. Biochemistry 34: 7 12.
95. Someya, Y.,, and A. Yamaguchi. 1997. Second-site suppressor mutations for the Arg70 substitution mutants of the Tn 10- encoded metal-tetracycline/H + antiporter of Escherichia coli. Biochim. Biophys. Acta 1322: 230 236.
96. Speer, B. S.,, L. Bedzyk,, and A. A. Salyers. 1991. Evidence that a novel tetracycline resistance gene found on two Bacteroides transposons encodes an NADP-requiring oxidoreductase. J. Bacteriol. 173: 176 183.
97. Speer, B. S.,, and A. A. Salyers. 1988. Characterization of a novel tetracycline resistance that functions only in aerobically grown Escherichia coli. J. Bacteriol. 170: 1423 1429.
98. Speer, B. S.,, and A. A. Salyers. 1989. Novel aerobic tetracycline resistance gene that chemically modifies tetracycline. J. Bacteriol. 171: 148 153.
99. Stasinopoulos, S. J.,, G. A. Farr,, and D. H. Bechhofer. 1998. Bacillus subtilis tetA(L) gene expression: evidence for regulation by translational reinitiation. Mol. Microbiol. 30: 923 932.
100. Tamura, N.,, S. Konishi,, S. Iwaki,, T. Kimura-Someya,, S. Nada,, and A. Yamaguchi. 2001. Complete cysteine-scanning mutagenesis and site-directed chemical modification of the Tn 10- encoded metal-tetracycline/H + antiporter. J. Biol. Chem. 276: 20330 20339.
101. Tamura, N.,, S. Konishi,, and A. Yamaguchi. 2003. Mechanisms of drug/H + antiport: complete cysteine-scanning mutagenesis and the protein engineering approach. Curr. Opin. Chem. Biol. 7: 570 579.
102. Tauch, A.,, S. Krieft,, A. Puhler,, and J. Kalinowski. 1999. The tetAB genes of the Corynebacterium striatum R-plasmid pTP10 encode an ABC transporter and confer tetracycline, oxytetracycline and oxacillin resistance in Corynebacterium glutamicum. FEMS Microbiol. Lett. 173: 203 209.
103. Teo, J. W.,, T. M. Tan,, and C. L. Poh. 2002. Genetic determinants of tetracycline resistance in Vibrio harveyi. Antimicrob. Agents Chemother. 46: 1038 1045.
104. Trieber, C. A.,, and D. E. Taylor. 2002. Mutations in the 16S rRNA genes of Helicobacter pylori mediate resistance to tetracycline. J. Bacteriol. 184: 2131 2140.
104a.. Truong-Bolduc, Q. C.,, P. M. Dunman,, J. Strahilevitz,, S. J. Projan,, and D. C. Hooper. 2005. MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus. J. Bacteriol. 187: 2395 2405.
105. Tuckman, M.,, P. J. Petersen,, and S. J. Projan. 2000. Mutations in the interdomain loop region of the tetA(A) tetracycline resistance gene increase efflux of minocycline and glycylcyclines. Microb. Drug Resist. 6: 277 282.
106. Vardy, E.,, I. T. Arkin,, K. E. Gottschalk,, H. R. Kaback,, and S. Schuldiner. 2004. Structural conservation in the major facilitator superfamily as revealed by comparative modeling. Protein Sci. 13: 1832 1840.
107. Varela, M. F.,, C. E. Sansom,, and J. K. Griffith. 1995. Mutational analysis and molecular modelling of an amino acid sequence motif conserved in antiporters but not symporters in a transporter superfamily. Mol. Memb. Biol. 12: 313 319.
108. Wang, W.,, A. A. Guffanti,, Y. Wei,, M. Ito,, and T. A. Krulwich. 2000. Two types of Bacillus subtilis tetA(L) deletion strains reveal the physiological importance of TetA(L) in K + acquisition as well as in Na +, alkali, and tetracycline resistance. J. Bacteriol. 182: 2088 2095.
109. Yamaguchi, A.,, K. Adachi,, T. Akasaka,, N. Ono,, and T. Sawai. 1991. Metal-tetracycline/H + antiporter of Escherichia coli encoded by a transposon Tn 10: histidine 257 plays an essential role in H + translocation. J. Biol. Chem. 266: 6045 6051.
110. Yamaguchi, A.,, T. Akasaka,, T. Kimura,, T. Sakai,, Y. Adachi,, and T. Sawai. 1993. Role of the conserved quartets of residues located in the N- and C-terminal halves of the transposon Tn 10-encoded metal-tetracycline/H + antiporter of Escherichia coli. Biochemistry 32: 5698 5704.
111. Yamaguchi, A.,, T. Akasaka,, N. Ono,, Y. Someya,, M. Nakatani,, and T. Sawai. 1992. Metal-tetracycline/H + antiporter of Escherichia coli encoded by transposon Tn 10. Roles of the aspartyl residues located in the putative transmembrane helices. J. Biol. Chem. 267: 7490 7498.
112. Yamaguchi, A.,, Y. Inagaki,, and T. Sawai. 1995. Second-site suppressor mutations for the Asp-66 → Cys mutant of the transposon Tn 10-encoded metal-tetracycline/H + antiporter of Escherichia coli. Biochemistry 34: 11800 6.
113. Yamaguchi, A.,, Y. Iwasaki-Ohba,, N. Ono,, M. Kaneko-Ohdera,, and T. Sawai. 1991. Stoichiometry of metal-tetracycline/ H + antiport mediated by transposon Tn 10-encoded tetracycline resistance protein in Escherichia coli. FEBS Lett. 282: 415 418.
114. Yamaguchi, A.,, R. O’yauchi,, Y. Someya,, T. Akasaka,, and T. Sawai. 1993. Second-site mutation of Ala-220 to Glu or Asp suppresses the mutation of Asp-285 to Asn in the transposon Tn 10-encoded metal-tetracycline/H + antiporter of Escherichia coli. J. Biol. Chem. 268: 26990 26995.
115. Yamaguchi, A.,, N. Ono,, T. Akasaka,, T. Noumi,, and T. Sawai. 1990. Metal-tetracycline/H + antiporter of Escherichia coli encoded by a transposon, Tn 10: the role of the conserved dipeptide, Ser65-Asp66 in tetracycline transport. J. Biol. Chem. 265: 15525 15530.
116. Yamaguchi, A.,, N. Ono,, T. Akasaka,, and T. Sawai. 1992. Serine residues responsible for tetracycline transport are on a vertical stripe including Asp-84 on one side of transmembrane helix 3 in transposon Tn 10-encoded tetracycline/H + antiporter of Escherichia coli. FEBS. Lett. 307: 229 232.
117. Yamaguchi, A.,, T. Samejima,, T. Kimura,, and T. Sawai. 1996. His257 is a uniquely important histidine residue for tetracycline/ H + antiport function but not mandatory for full activity of the transposon Tn 10-encoded metal-tetracycline/H + antiporter. Biochemistry 35: 4359 4364.
118. Yamaguchi, A.,, Y. Shiina,, E. Fujihira,, T. Sawai,, N. Noguchi,, and M. Sasatsu. 1995. The tetracycline efflux protein encoded by the tet(K) gene from Staphylococcus aureus is a metaltetracycline/ H + antiporter. FEBS Lett. 365: 193 197.
119. Yamaguchi, A.,, Y. Someya,, and T. Sawai. 1993. The in vivo assembly and function of the N- and C-terminal halves of the Tn 10-encoded TetA protein in Escherichia coli. FEBS Lett. 324: 131 135.
120. Yamaguchi, A.,, Y. Someya,, and T. Sawai. 1992. Metaltetracycline/ H + antiporter of Escherichia coli encoded by transposon Tn 10. The role of a conserved sequence motif, GXXXXRXGRR, in a putative cytoplasmic loop between helices 2 and 3. J. Biol. Chem. 267: 19155 19162.
121. Yamaguchi, A.,, T. Udagawa,, and T. Sawai. 1990. Transport of divalent cations with tetracycline as mediated by the transposon Tn 10-encoded tetracycline resistance protein. J. Biol. Chem. 265: 4809 4813.
122. Yang, H. L.,, G. Zubay,, and S. B. Levy. 1976. Synthesis of an R plasmid protein associated with tetracycline resistance is negatively regulated. Proc. Natl. Acad. Sci. USA 73: 1509 1512.
123. Yang, W.,, I. F. Moore,, K. P. Koteva,, D. C. Bareich,, D. W. Hughes,, and G. D. Wright. 2004. TetX is a flavin-dependent monooxygenase conferring resistance to tetracycline antibiotics. J. Biol. Chem. 279: 52346 52352.
124. Yin, C. C.,, M. L. Aldema-Ramos,, M. I. Borges-Walmsley,, R. W. Taylor,, A. R. Walmsley,, S. B. Levy,, and P. A. Bullough. 2000. The quarternary molecular architecture of TetA, a secondary tetracycline transporter from Escherichia coli. Mol. Microbiol. 38: 482 492.
125. Zhuang, J.,, G. G. Prive,, G. E. Werner,, P. Ringler,, H. R. Kaback,, and A. Engel. 1999. Two-dimensional crystallization of Escherichia coli lactose permease. J. Struct. Biol. 125: 63 75.

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