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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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Volume 395, Issue 5


Tetracycline antibiotics and resistance mechanisms

Fabian Nguyen
  • Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
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/ Agata L. Starosta
  • Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
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/ Stefan Arenz
  • Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
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/ Daniel Sohmen
  • Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
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/ Alexandra Dönhöfer
  • Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
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/ Daniel N. Wilson
  • Corresponding author
  • Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
  • Center for Integrated Protein Science Munich (CiPSM), University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany
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Published Online: 2014-02-05 | DOI: https://doi.org/10.1515/hsz-2013-0292


The ribosome and protein synthesis are major targets within the cell for inhibition by antibiotics, such as the tetracyclines. The tetracycline family of antibiotics represent a large and diverse group of compounds, ranging from the naturally produced chlortetracycline, introduced into medical usage in the 1940s, to second and third generation semi-synthetic derivatives of tetracycline, such as doxycycline, minocycline and more recently the glycylcycline tigecycline. Here we describe the mode of interaction of tetracyclines with the ribosome and mechanism of action of this class of antibiotics to inhibit translation. Additionally, we provide an overview of the diverse mechanisms by which bacteria obtain resistance to tetracyclines, ranging from efflux, drug modification, target mutation and the employment of specialized ribosome protection proteins.

Keywords: glycylcycline; resistance; ribosome; tetracycline; tigecycline; translation


  • Agwuh, K.N. and MacGowan, A. (2006). Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J. Antimicrob. Chemother. 58, 256–265.Google Scholar

  • Backus, E.J., Duggar, B.M., and Campbell, T.H. (1954). Variation in Streptomyces aureofaciens. Ann. NY Acad. Sci. 60, 86–101.Google Scholar

  • Barden, T.C., Buckwalter, B.L., Testa, R.T., Petersen, P.J., and Lee, V.J. (1994). “Glycylcyclines”. 3. 9-Aminodoxycyclinecarboxamides. J. Med. Chem. 37, 3205–3211.Google Scholar

  • Barile, S., Devirgiliis, C., and Perozzi, G. (2012). Molecular characterization of a novel mosaic tet(S/M) gene encoding tetracycline resistance in foodborne strains of Streptococcus bovis. Microbiology 158, 2353–2362.Google Scholar

  • Bauer, G., Berens, C., Projan, S., and Hillen, W. (2004). Comparison of tetracycline and tigecycline binding to ribosomes mapped by dimethylsulphate and drug-directed Fe2+ cleavage of 16S rRNA. J. Antimicrob. Chemother. 53, 592–599.Google Scholar

  • Ben-Shem, A., Garreau de Loubresse, N., Melnikov, S., Jenner, L., Yusupova, G., and Yusupov, M. (2011). The structure of the eukaryotic ribosome at 3.0 Å resolution. Science 334, 1524–1529.Google Scholar

  • Bergeron, J., Ammirati, M., Danley, D., James, L., Norcia, M., Retsema, J., Strick, C.A., Su, W.G., Sutcliffe, J., and Wondrack, L. (1996). Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection. Antimicrob. Agents Chemother. 40, 2226–2228.Google Scholar

  • Blackwood, R.K., Beereboom, J.J., Rennhard, H.H., von Wittenau, M.S., and Stephens, C.R. (1961). 6-methylenetetracyclines.1 I. a new class of tetracycline antibiotics. J. Am. Chem. Soc. 83, 2773–2775.Google Scholar

  • Blanchard, S.C., Gonzalez, R.L., Kim, H.D., Chu, S., and Puglisi, J.D. (2004). tRNA selection and kinetic proofreading in translation. Nat. Struct. Mol. Biol. 11, 1008–1014.CrossrefGoogle Scholar

  • Boothe, J.H., Kende, A.S., Fields, T.L., and Wilkinson, R.G. (1959). Total synthesis of tetracyclines. I. (±)-dedimethylamino-12a-deoxy-6-demethylanhydrochlortetracycline. J. Am. Chem. Soc. 81, 1006–1007.Google Scholar

  • Bradford, P.A., and Jones, C.H. (2012). Tetracyclines. In: Antibiotic Discovery and Development, Dougherty, T.J. and Puccim, M.J., eds. (New York: Springer), pp. 147–179.Google Scholar

  • Brodersen, D.E., Clemons, W.M., Carter, A.P., Morgan-Warren, R.J., Wimberly, B.T., and Ramakrishnan, V. (2000). The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103, 1143–1154.Google Scholar

  • Budkevich, T.V., El’skaya, A.V., and Nierhaus, K.H. (2008). Features of 80S mammalian ribosome and its subunits. Nucleic Acids Res. 36, 4736–4744.CrossrefGoogle Scholar

  • Burdett, V. (1991). Purification and characterization of Tet(M), a protein that renders ribosomes resistant to tetracycline. J. Biol. Chem. 266, 2872–2877.Google Scholar

  • Burdett, V. (1993). transfer-RNA modification activity is necessary for Tet(M)-mediated tetracycline resistance. J. Bacteriol. 175, 7209–7215.Google Scholar

  • Burdett, V. (1996). Tet(M)-promoted release of tetracycline from ribosomes is GTP dependent. J. Bacteriol. 178, 3246–3251.Google Scholar

  • Caryl, J.A., Cox, G., Trimble, S., and O’Neill, A.J. (2012). “tet(U)” is not a tetracycline resistance determinant. Antimicrob. Agents Chemother. 56, 3378–3379.Google Scholar

  • Chopra, I. and Roberts, M. (2001). Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol. Mol. Biol. Rev. 65, 232–260.CrossrefGoogle Scholar

  • Connell, S.R., Trieber, C.A., Stelzl, U., Einfeldt, E., Taylor, D.E., and Nierhaus, K.H. (2002). The tetracycline resistance protein Tet(O) perturbs the conformation of the ribosomal decoding centre. Mol. Microbiol. 45, 1463–1472.CrossrefGoogle Scholar

  • Connell, S.R., Tracz, D.M., Nierhaus, K.H., and Taylor, D.E. (2003a). Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrob. Agents Chemother. 47, 3675–3681.Google Scholar

  • Connell, S.R., Trieber, C.A., Dinos, G.P., Einfeldt, E., Taylor, D.E., and Nierhaus, K.H. (2003b). Mechanism of Tet(O)-mediated tetracycline resistance. EMBO J. 22, 945–953.CrossrefGoogle Scholar

  • Conover, L.H., Moreland, W.T., English, A.R., Stephens, C.R., and Pilgrim, F.J. (1953). Terramycin. Xi. Tetracycline. J. Am. Chem. Soc. 75, 4622–4623.CrossrefGoogle Scholar

  • Dailidiene, D., Bertoli, M.T., Miciuleviciene, J., Mukhopadhyay, A.K., Dailide, G., Pascasio, M.A., Kupcinskas, L., and Berg, D.E. (2002). Emergence of tetracycline resistance in Helicobacter pylori: multiple mutational changes in 16S ribosomal DNA and other genetic loci. Antimicrob. Agents Chemother. 46, 3940–3946.Google Scholar

  • Dantley, K., Dannelly, H., and Burdett, V. (1998). Binding interaction between Tet(M) and the ribosome: requirements for binding. J. Bacteriol. 180, 4089–4092.Google Scholar

  • Dönhöfer, A., Franckenberg, S., Wickles, S., Berninghausen, O., Beckmann, R., and Wilson, D.N. (2012). Structural basis for TetM-mediated tetracycline resistance. Proc. Natl. Acad. Sci. USA 109, 16900–16905.Google Scholar

  • Doyle, D., McDowall, K.J., Butler, M.J., and Hunter, I.S. (1991). Characterization of an oxytetracycline-resistance gene, otrA, of Streptomyces rimosus. Mol. Microbiol. 5, 2923–2933.CrossrefGoogle Scholar

  • Draper, M.P., Weir, S., Macone, A., Donatelli, J., Trieber, C.A., Tanaka, S.K., and Levy, S.B. (2013). The mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob. Agents Chemother. Sep 16. [Epub ahead of print] doi: 10.1128/AAC.01066-13.CrossrefGoogle Scholar

  • Duggar, B.M. (1948). Aureomycin; a product of the continuing search for new antibiotics. Ann. NY Acad. Sci. 51, 177–181.CrossrefGoogle Scholar

  • Esberg, B. and Bjork, G.R. (1995). The methylthio group (ms(2)) of N-6-(4-hydroxyisopentenyl)-2-methylthioadenosine (ms(2)io(6)A) present next to the anticodon contributes to the decoding efficiency of the tRNA. J. Bacteriol. 177, 1967–1975.Google Scholar

  • Finlay, A.C., Hobby, G.L., P’an, S.Y., Regna, P.P., Routien, J.B., Seeley, D.B., Shull, G.M., Sobin, B.A., Solomons, I.A., Vinson, J.W., et al. (1950). Terramycin, a new antibiotic. Science 111, 85.Google Scholar

  • Gale, E.F., Cundliffe, E., Reynolds, P.E., Richmond, M.H., and Waring, M.J. (1981). Antibiotic inhibitors of ribosome function. In: The Molecular Basis of Antibiotic Action (Bristol, UK: John Wiley and Sons), pp. 278–379.Google Scholar

  • Gao, Y.G., Selmer, M., Dunham, C.M., Weixlbaumer, A., Kelley, A.C., and Ramakrishnan, V. (2009). The structure of the ribosome with elongation factor G trapped in the posttranslocational state. Science 326, 694–699.Google Scholar

  • Geggier, P., Dave, R., Feldman, M.B., Terry, D.S., Altman, R.B., Munro, J.B., and Blanchard, S.C. (2010). Conformational sampling of aminoacyl-tRNA during selection on the bacterial ribosome. J. Mol. Biol. 399, 576–595.Google Scholar

  • Gerrits, M.M., de Zoete, M.R., Arents, N.L., Kuipers, E.J., and Kusters, J.G. (2002). 16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori. Antimicrob. Agents Chemother. 46, 2996–3000.Google Scholar

  • Gerrits, M.M., Berning, M., Van Vliet, A.H., Kuipers, E.J., and Kusters, J.G. (2003). Effects of 16S rRNA gene mutations on tetracycline resistance in Helicobacter pylori. Antimicrob. Agents Chemother. 47, 2984–2986.Google Scholar

  • Grewal, J., Manavathu, E.K., and Taylor, D.E. (1993). Effect of mutational alteration of Asn-128 in the putative GTP-binding domain of tetracycline resistance determinant Tet(O) from Campylobacter jejuni. Antimicrob. Agents Chemother. 37, 2645–2649.Google Scholar

  • Grossman, T.H., Starosta, A.L., Fyfe, C., O’Brien, W., Rothstein, D.M., Mikolajka, A., Wilson, D.N., and Sutcliffe, J.A. (2012). Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob. Agents Chemother. 56, 2559–2564.Google Scholar

  • Guay, G.G., Tuckman, M., and Rothstein, D.M. (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.Google Scholar

  • Guillaume, G., Ledent, V., Moens, W., and Collard, J.M. (2004). Phylogeny of efflux-mediated tetracycline resistance genes and related proteins revisited. Microb. Drug Resist. 10, 11–26.CrossrefGoogle Scholar

  • Hillen, W. and Berens, C. (1994). Mechanisms underlying expression of Tn10 encoded tetracycline resistance. Annu. Rev. Microbiol. 48, 345–369.CrossrefGoogle Scholar

  • Hinrichs, W., Kisker, C., Duvel, M., Muller, 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.Google Scholar

  • Hochstein, F.A., Stephens, C.R., Conover, L.H., Regna, P.P., Pasternack, R., Gordon, P.N., Pilgrim, F.J., Brunings, K.J., and Woodward, R.B. (1953). The structure of terramycin1,2. J. Am. Chem. Soc. 75, 5455–5475.CrossrefGoogle Scholar

  • Jenner, L., Starosta, A.L., Terry, D.S., Mikolajka, A., Filonava, L., Yusupov, M., Blanchard, S.C., Wilson, D.N., and Yusupova, G. (2013). Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis. Proc. Natl. Acad. Sci. USA 110, 3812–3816.Google Scholar

  • Jiang, D., Zhao, Y., Wang, X., Fan, J., Heng, J., Liu, X., Feng, W., Kang, X., Huang, B., Liu, J., et al. (2013). Structure of the YajR transporter suggests a transport mechanism based on the conserved motif A. Proc. Natl. Acad. Sci. USA 110, 14664–14669.Google Scholar

  • Kisker, C., Hinrichs, W., Tovar, K., Hillen, W., and Saenger, W. (1995). The complex formed between Tet repressor and tetracycline-Mg2+ reveals mechanism of antibiotic resistance. J. Mol. Biol. 247, 260–280.Google Scholar

  • Li, W., Atkinson, G.C., Thakor, N.S., Allas, U., Lu, C.C., Chan, K.Y., Tenson, T., Schulten, K., Wilson, K.S., Hauryliuk, V., et al. (2013). Mechanism of tetracycline resistance by ribosomal protection protein Tet(O). Nat. Commun. 4, 1477.CrossrefGoogle Scholar

  • Martell, M.J., Jr. and Boothe, J.H. (1967). The 6-deoxytetracyclines. VII. Alkylated aminotetracyclines possessing unique antibacterial activity. J. Med. Chem. 10, 44–46.CrossrefGoogle Scholar

  • McCormick, J.R.D., Sjolander, N.O., Hirsch, U., Jensen, E.R., and Doerschuk, A.P. (1957). A new family of antibiotics: the demethyltetracyclines. J. Am. Chem. Soc. 79, 4561–4563.CrossrefGoogle Scholar

  • McCormick, J.R.D., Hirsch, U., Sjolander, N.O., and Doerschuk, A.P. (1960). Cosynthesis of tetracyclines by pairs of Streptomyces aureofaciens mutants. J. Am. Chem. Soc. 82, 5006–5007.CrossrefGoogle Scholar

  • Mikolajka, A., Liu, H., Chen, Y., Starosta, A.L., Marquez, V., Ivanova, M., Cooperman, B.S., and Wilson, D.N. (2011). Differential effects of thiopeptide and orthosomycin antibiotics on translational GTPases. Chem. Biol. 18, 589–600.CrossrefGoogle Scholar

  • Moazed, D. and Noller, H.F. (1987). Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature 327, 389–394.Google Scholar

  • Moore, I.F., Hughes, D.W., and Wright, G.D. (2005). Tigecycline is modified by the flavin-dependent monooxygenase TetX. Biochemistry 44, 11829–11835.Google Scholar

  • Nelson, M.L. (2001). The chemistry and cellular biology of the tetracyclines. In: Tetracyclines in Biology, Chemistry and Medicine, M.L. Nelson, W. Hillen, and R.A. Greenwald, eds. (Switzerland: Birkhäuser Verlag), pp. 3–63.Google Scholar

  • Nelson, M.L. and Levy, S.B. (2011). The history of the tetracyclines. Ann. N.Y. Acad. Sci. 1241, 17–32.Google Scholar

  • Nelson, M.L., Ismail, M.Y., McIntyre, L., Bhatia, B., Viski, P., Hawkins, P., Rennie, G., Andorsky, D., Messersmith, D., Stapleton, K., et al. (2003). Versatile and facile synthesis of diverse semisynthetic tetracycline derivatives via Pd-catalyzed reactions. J. Org. Chem. 68, 5838–5851.CrossrefGoogle Scholar

  • Nonaka, L., Connell, S.R., and Taylor, D.E. (2005). 16S rRNA mutations that confer tetracycline resistance in Helicobacter pylori decrease drug binding in Escherichia coli ribosomes. J. Bacteriol. 187, 3708–3712.Google Scholar

  • Olson, M.W., Ruzin, A., Feyfant, E., Rush, T.S., 3rd, O’Connell, J., and Bradford, P.A. (2006). Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob. Agents Chemother. 50, 2156–2166.Google Scholar

  • Orth, P., Schnappinger, D., Sum, P.E., Ellestad, G.A., Hillen, W., Saenger, W., and Hinrichs, W. (1999). Crystal structure of the tet repressor in complex with a novel tetracycline, 9-(N,N-dimethylglycylamido)- 6-demethyl-6-deoxy-tetracycline. J. Mol. Biol. 285, 455–461.Google Scholar

  • Orth, P., Schnappinger, D., Hillen, W., Saenger, W., and Hinrichs, W. (2000). Structural basis of gene regulation by the tetracycline inducible Tet repressor-operator system. Nat. Struct. Biol. 7, 215–219.CrossrefGoogle Scholar

  • Perlman, D., Heuser, L.J., Dutcher, J.D., Barrett, J.M., and Boska, J.A. (1960). Biosynthesis of tetracycline by 5-hydroxy-tetracycline-producing cultures of Streptomyces rimosus. J. Bacteriol. 80, 419–420.Google Scholar

  • Petersen, P.J., Jacobus, N.V., Weiss, W.J., Sum, P.E., and Testa, R.T. (1999). In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob. Agents Chemother. 43, 738–744.Google Scholar

  • Piddock, L.J. (2006). Multidrug-resistance efflux pumps-not just for resistance. Nat. Rev. Microbiol. 4, 629–636.CrossrefGoogle Scholar

  • Pioletti, M., Schlunzen, F., Harms, J., Zarivach, R., Gluhmann, M., Avila, H., Bashan, A., Bartels, H., Auerbach, T., Jacobi, C., et al. (2001). Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J. 20, 1829–1839.CrossrefGoogle Scholar

  • Ridenhour, M.B., Fletcher, H.M., Mortensen, J.E., and Daneo-Moore, L. (1996). A novel tetracycline-resistant determinant, tet(U), is encoded on the plasmid pKq10 in Enterococcus faecium. Plasmid 35, 71–80.Google Scholar

  • Roberts, M.C. (1994). Epidemiology of tetracycline-resistance determinants. Trends Microbiol. 2, 353–357.CrossrefGoogle Scholar

  • Roberts, M.C. (1996). Tetracycline resistance determinants: Mechanisms of action, regulation of expression, genetic mobility, and distribution. FEMS Microbiol. Rev. 19, 1–24.CrossrefGoogle Scholar

  • Ross, J.I., Eady, E.A., Cove, J.H., and Cunliffe, W.J. (1998). 16S rRNA mutation associated with tetracycline resistance in a Gram-positive bacterium. Antimicrob. Agents Chemother. 42, 1702–1705.Google Scholar

  • Saenger, W., Orth, P., Kisker, C., Hillen, W., and Hinrichs, W. (2000). The tetracycline repressor-a paradigm for a biological switch. Angew Chem. Int. Ed. Engl. 39, 2042–2052.CrossrefGoogle Scholar

  • Schmeing, T.M., Voorhees, R.M., Kelley, A.C., Gao, Y.G., Murphy, F.V.T., Weir, J.R., and Ramakrishnan, V. (2009). The crystal structure of the ribosome bound to EF-Tu and aminoacyl-tRNA. Science 326, 688–694.Google Scholar

  • Söding, J., Biegert, A., and Lupas, A.N. (2005). The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 33, W244–W248.CrossrefGoogle Scholar

  • Sohmen, D., Harms, J.M., Schlunzen, F., and Wilson, D.N. (2009a). Enhanced SnapShot: Antibiotic inhibition of protein synthesis II. Cell 139, 212–212 e211.Google Scholar

  • Sohmen, D., Harms, J.M., Schlunzen, F., and Wilson, D.N. (2009b). SnapShot: antibiotic inhibition of protein synthesis I. Cell 138, 1248 e1241.Google Scholar

  • Spahn, C.M., Blaha, G., Agrawal, R.K., Penczek, P., Grassucci, R.A., Trieber, C.A., Connell, S.R., Taylor, D.E., Nierhaus, K.H., and Frank, J. (2001). Localization of the ribosomal protection protein Tet(O) on the ribosome and the mechanism of tetracycline resistance. Mol. Cell 7, 1037–1045.Google Scholar

  • Speer, B.S., Bedzyk, L., and Salyers, A.A. (1991). Evidence that a novel tetracycline resistance gene found on two Bacteroides transposons encodes an NADP-requiring oxidoreductase. J. Bacteriol. 173, 176–183.Google Scholar

  • Starosta, A.L., Qin, H., Mikolajka, A., Leung, G.Y., Schwinghammer, K., Nicolaou, K.C., Chen, D.Y., Cooperman, B.S., and Wilson, D.N. (2009). Identification of distinct thiopeptide-antibiotic precursor lead compounds using translation machinery assays. Chem Biol 16, 1087–1096.CrossrefGoogle Scholar

  • Stephens, C.R., Conover, L.H., Hochstein, F.A., Regna, P.P., Pilgrim, F.J., Brunings, K.J., and Woodward, R.B. (1952). Terramycin. VIII. Structure of aureomycin and terramycin. J. Am. Chem. Soc. 74, 4976–4977.CrossrefGoogle Scholar

  • Stephens, C.R., Conover, L.H., Pasternack, R., Hochstein, F.A., Moreland, W.T., Regna, P.P., Pilgrim, F.J., Brunings, K.J., and Woodward, R.B. (1954). The structure of Aureomycin1. J. Am. Chem. Soc. 76, 3568–3575.CrossrefGoogle Scholar

  • Stephens, C.R., Beereboom, J.J., Rennhard, H.H., Gordon, P.N., Murai, K., Blackwood, R.K., and von Wittenau, M.S. (1963). 6-Deoxytetracyclines. IV.1,2 Preparation, C-6 Stereochemistry, and Reactions. J. Am. Chem. Soc. 85, 2643–2652.Google Scholar

  • Sum, P.E., Lee, V.J., Testa, R.T., Hlavka, J.J., Ellestad, G.A., Bloom, J.D., Gluzman, Y., and Tally, F.P. (1994). Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J. Med. Chem. 37, 184–188.CrossrefGoogle Scholar

  • Sun, C., Wang, Q., Brubaker, J.D., Wright, P.M., Lerner, C.D., Noson, K., Charest, M., Siegel, D.R., Wang, Y.M., and Myers, A.G. (2008). A robust platform for the synthesis of new tetracycline antibiotics. J. Am. Chem. Soc. 130, 17913–17927.Google Scholar

  • Sun, C., Hunt, D.K., Clark, R.B., Lofland, D., O’Brien, W.J., Plamondon, L., and Xiao, X.Y. (2010). Synthesis and antibacterial activity of pentacyclines: a novel class of tetracycline analogs. J. Med. Chem. 54, 3704–3731.CrossrefGoogle Scholar

  • Tally, F.T., Ellestad, G.A., and Testa, R.T. (1995). Glycylcyclines: a new generation of tetracyclines. J. Antimicrob. Chemother. 35, 449–452.Google Scholar

  • Taylor, D.E., Jerome, L.J., Grewal, J., and Chang, N. (1995). Tet(O), a protein that mediates ribosomal protection to tetracycline, binds, and hydrolyses GTP. Can. J. Microbiol. 41, 965–970.CrossrefGoogle Scholar

  • Taylor, D.E., Trieber, C.A., Trescher, G., and Bekkering, M. (1998). Host mutations (miaA and rpsL) reduce tetracycline resistance mediated by Tet(O) and Tet(M). Antimicrob. Agents Chemother. 42, 59–64.Google Scholar

  • Testa, R.T., Petersen, P.J., Jacobus, N.V., Sum, P.E., Lee, V.J., and Tally, F.P. (1993). In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines. Antimicrob. Agents Chemother. 37, 2270–2277.Google Scholar

  • Thaker, M., Spanogiannopoulos, P., and Wright, G.D. (2010). The tetracycline resistome. Cell. Mol. Life Sci. 67, 419–431.Google Scholar

  • Trieber, C.A. and Taylor, D.E. (2002). Mutations in the 16S rRNA genes of Helicobacter pylori mediate resistance to tetracycline. J. Bacteriol. 184, 2131–2140.Google Scholar

  • Trieber, C.A., Burkhardt, N., Nierhaus, K.H., and Taylor, D.E. (1998). Ribosomal protection from tetracycline mediated by Tet(O) interaction with ribosomes is GTP-dependent. Biol. Chem. 379, 847–855.Google Scholar

  • Vacher, J., Grosjean, H., Houssier, C., and Buckingham, R.H. (1984). The effect of point mutations affecting Escherichia coli tryptophan tRNA on anticodon-anticodon interactions and on UGA suppression. J. Mol. Biol. 177, 329–342.Google Scholar

  • Volkers, G., Palm, G.J., Weiss, M.S., Wright, G.D., and Hinrichs, W. (2011). Structural basis for a new tetracycline resistance mechanism relying on the TetX monooxygenase. FEBS Lett. 585, 1061–1066.Google Scholar

  • Volkers, G., Damas, J.M., Palm, G.J., Panjikar, S., Soares, C.M., and Hinrichs, W. (2013). Putative dioxygen-binding sites and recognition of tigecycline and minocycline in the tetracycline-degrading monooxygenase TetX. Acta Crystallogr. D Biol. Crystallogr. 69, 1758–1767.CrossrefGoogle Scholar

  • Voorhees, R.M., Weixlbaumer, A., Loakes, D., Kelley, A.C., and Ramakrishnan, V. (2009). Insights into substrate stabilization from snapshots of the peptidyl transferase center of the intact 70S ribosome. Nat. Struct. Mol. Biol. 16, 528–533.CrossrefGoogle Scholar

  • White, J.P. and Cantor, C.R. (1971). Role of magnesium in the binding of tetracycline to Escherichia coli ribosomes. J. Mol. Biol. 58, 397–400.CrossrefGoogle Scholar

  • Wilson, D.N. (2009). The A-Z of bacterial translation inhibitors. Crit. Rev. Biochem. Mol. Biol. 44, 393–433.CrossrefGoogle Scholar

  • Wilson, D.N. (2013). Ribosome-targeting antibiotics and bacterial resistance mechanisms. Nat. Rev. Microbiol., 12, 35–48.CrossrefGoogle Scholar

  • Yang, W., Moore, I.F., Koteva, K.P., Bareich, D.C., Hughes, D.W., and Wright, G.D. (2004). TetX is a flavin-dependent monooxygenase conferring resistance to tetracycline antibiotics. J. Biol. Chem. 279, 52346–52352.Google Scholar

About the article

Corresponding author: Daniel N. Wilson, Gene Center and Department of Biochemistry, University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany; and Center for Integrated Protein Science Munich (CiPSM), University of Munich, Feodor-Lynenstr. 25, D-81377 Munich, Germany, e-mail:

Received: 2013-12-06

Accepted: 2014-01-30

Published Online: 2014-02-05

Published in Print: 2014-05-01

Citation Information: Biological Chemistry, Volume 395, Issue 5, Pages 559–575, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2013-0292.

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