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  • Review Article
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The bacterial ribosome as a target for antibiotics

Nature Reviews Microbiology volume 3, pages 870–881 (2005)Cite this article

Key Points

  • A large proportion of clinically useful antibiotics exert their antimicrobial effects by blocking protein synthesis on the ribosome. The bacterial ribosome is a ribonucleoprotein complex of about 2.5 million Daltons, and is composed of two subunits that are named after their sedimentation values of 30S and 50S.

  • The molecular details of the ribosome have recently been determined by X-ray crystallography. Different organisms have been used as the source of ribosomal particles for crystallization.

  • Well resolved structures have been obtained for the 30S subunit and the intact ribosome from the bacterium Thermus thermophilus. The best resolved structures for the 50S subunit come from the bacterium Deinococcus radiodurans and the archaeon Haloarcula marismortui.

  • These crystal structures reveal the molecular details of the antibiotic-binding sites. Furthermore, they explain many earlier observations from biochemical and genetic studies including: how drugs exercise their inhibitory effects; how some drugs in combination enhance or impede each other's binding; and how alterations to ribosomal components confer resistance.

  • The antibiotic-binding sites are located within functionally important structures in the ribosomal RNA (rRNA). Antibiotic resistance is often conferred by base substitution or methylation at these sites in the rRNA. However, resistance can also be conferred by mutations in ribosomal proteins that influence these rRNA structures.

  • Resistance can be counteracted by equipping current antibiotics with new chemical substituents that improve their binding. Perhaps even greater potential, which is presently unrealized, lies in the rational design of novel compounds that target unexploited sites within the ribosome structure.

Abstract

Many clinically useful antibiotics exert their antimicrobial effects by blocking protein synthesis on the bacterial ribosome. The structure of the ribosome has recently been determined by X-ray crystallography, revealing the molecular details of the antibiotic-binding sites. The crystal data explain many earlier biochemical and genetic observations, including how drugs exercise their inhibitory effects, how some drugs in combination enhance or impede each other's binding, and how alterations to ribosomal components confer resistance. The crystal structures also provide insight as to how existing drugs might be derivatized (or novel drugs created) to improve binding and circumvent resistance.

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Figure 1: Binding sites of antibiotics on the bacterial ribosome.
Figure 2: Chemical structures of a selection of ribosome-targeting drugs.
Figure 3: The decoding site at the interface of the 30S ribosomal subunit.
Figure 4: Binding sites of macrolide, lincosamide, streptogramin B (MLSB) antibiotics within the 50S subunit tunnel.

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References

  1. Vázquez, D. Inhibitors of Protein Biosynthesis (Springer–Verlag, Berlin, 1979).

    Book  Google Scholar 

  2. Gale, E. F., Cundliffe, E., Reynolds, P. E., Richmond, M. H. & Waring, M. J. The Molecular Basis of Antibiotic Action (John Wiley and Sons, London, 1981).

    Google Scholar 

  3. Spahn, C. M. & Prescott, C. D. Throwing a spanner in the works: antibiotics and the translation apparatus. J. Mol. Med. 74, 423–439 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Mankin, A. S. Ribosomal antibiotics. Mol. Biol. 35, 509–520 (2001).

    Article  CAS  Google Scholar 

  5. Lake, J. A. Ribosome structure determined by electron microscopy of Escherichia coli small subunits, large subunits and monomeric ribosomes. J. Mol. Biol. 105, 131–139 (1976).

    Article  CAS  PubMed  Google Scholar 

  6. Tischendorf, G. W., Zeichhardt, H. & Stoffler, G. Architecture of the Escherichia coli ribosome as determined by immune electron microscopy. Proc. Natl Acad. Sci. USA 72, 4820–4824 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Boublik, M., Hellmann, W. & Kleinschmidt, A. K. Size and structure of Escherichia coli ribosomes by electron microscopy. Cytobiologie 14, 293–300 (1977).

    Google Scholar 

  8. Pape, T., Stark, H., Matadeen, R., Orlova, E. V. & van Heel, M. in The Ribosome: Structure, Function, Antibiotics and Cellular Interactions (eds Garrett, R. A. et al.) 37–44 (American Society for Microbiology, Washington DC, 2000).

    Book  Google Scholar 

  9. Agrawal, R. K. & Frank, J. Structural studies of the translational apparatus. Curr. Opin. Struct. Biol. 9, 215–221 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Frank, J. et al. The role of tRNA as a molecular spring in decoding, accommodation, and peptidyl transfer. FEBS Lett. 579, 959–962 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Valle, M. et al. Visualizing tmRNA entry into a stalled ribosome. Science 300, 127–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Valle, M. et al. Incorporation of aminoacyl-tRNA into the ribosome as seen by cryo-electron microscopy. Nature Struct. Biol. 10, 899–906 (2003). References 11 and 12 illustrate the power of the cryo-EM technique for viewing the ribosome at isolated steps in the translation process.

    Article  CAS  PubMed  Google Scholar 

  13. Noller, H. F., Hoffarth, V. & Zimniak, L. Unusual resistance of peptidyl transferase to protein extraction procedures. 256, 1416–1419 (1992).

  14. Green, R., Switzer, C. & Noller, H. F. Ribosome-catalyzed peptide-bond formation with an A-site substrate covalently linked to 23S ribosomal RNA. Science 280, 286–289 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, B. & Cech, T. R. Peptide bond formation by in vitro selected ribozymes. Nature 390, 96–100 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Nissen, P., Hansen, J., Ban, N., Moore, P. B. & Steitz, T. A. The structural basis of ribosome activity in peptide bond synthesis. Science 289, 920–930 (2000). The first structural data strongly indicating that peptide-bond formation is RNA-catalysed, and implicating 23S rRNA nucleotide A2451 in this process.

    Article  CAS  PubMed  Google Scholar 

  17. Bashan, A. et al. Structural basis of the ribosomal machinery for peptide bond formation, translocation, and nascent chain progression. Mol. Cell 11, 91–102 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Moore, P. B. & Steitz, T. A. The structural basis of large ribosomal subunit function. Annu. Rev. Biochem. 72, 813–850 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Sievers, A., Beringer, M., Rodnina, M. V. & Wolfenden, R. The ribosome as an entropy trap. Proc. Natl Acad. Sci. USA 101, 7897–7901 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Youngman, E. M., Brunelle, J. L., Kochaniak, A. B. & Green, R. The active site of the ribosome is composed of two layers of conserved nucleotides with distinct roles in peptide bond formation and peptide release. Cell 117, 589–599 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Erlacher, M. D. et al. Chemical engineering of the peptidyl transferase center reveals an important role of the 2′-hydroxyl group of A2451. Nucleic Acids Res. 33, 1618–1627 (2005). A cleverly designed biochemical/molecular genetic study of peptide-bond formation and the role of the nucleotide A2451 ribose. This article's introduction concisely sums up previous research and discussions on this topic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yonath, A., Mussig, J. & Wittmann, H. G. Parameters for crystal growth of ribosomal subunits. J. Cell. Biochem. 19, 145–155 (1982).

    Article  CAS  PubMed  Google Scholar 

  23. Trakhanov, S. et al. Preliminary X-ray investigation of 70 S ribosome crystals from Thermus thermophilus. J. Mol. Biol. 209, 327–328 (1989).

    Article  CAS  PubMed  Google Scholar 

  24. von Bohlen, K. et al. Characterization and preliminary attempts for derivatization of crystals of large ribosomal subunits from Haloarcula marismortui diffracting to 3 Å resolution. J. Mol. Biol. 222, 11–15 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Yusupov, M. M., Garber, M. B., Vasiliev, V. D. & Spirin, A. S. Thermus thermophilus ribosomes for crystallographic studies. Biochimie 73, 887–897 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Liljas, A. Structural aspects of protein synthesis (World Scientific, Singapore, 2004).

    Book  Google Scholar 

  27. Wimberly, B. T. et al. Structure of the 30S ribosomal subunit. Nature 407, 327–339 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Schluenzen, F. et al. Structure of functionally activated small ribosomal subunit at 3.3 Å resolution. Cell 102, 615–623 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Yusupov, M. M. et al. Crystal structure of the ribosome at 5.5 Å resolution. Science 292, 883–896 (2001). Describes the crystal structures of both ribosomal subunits in functional complexes, and reveals essential details of tRNA interactions and how the ribosome works.

    Article  CAS  PubMed  Google Scholar 

  30. Yusupova, G. Z., Yusupov, M. M., Cate, J. H. & Noller, H. F. The path of messenger RNA through the ribosome. Cell 106, 233–241 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Ban, N., Nissen, P., Hansen, J., Moore, P. B. & Steitz, T. A. The complete atomic structure of the large ribosomal subunit at 2.4 Å resolution. Science 289, 905–920 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Harms, J. et al. High resolution structure of the large ribosomal subunit from a mesophilic eubacterium. Cell 107, 679–688 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Vila-Sanjurjo, A. et al. X-ray crystal structures of the WT and a hyper-accurate ribosome from Escherichia coli. Proc. Natl Acad. Sci. USA 100, 8682–8687 (2003). First structure of E. coli ribosomes, which had previously been thought to be refractory to crystallographic analysis. Presently at low resolution, but more highly resolved data are on the way.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Klein, D. J., Moore, P. B. & Steitz, T. A. The roles of ribosomal proteins in the structure assembly, and evolution of the large ribosomal subunit. J. Mol. Biol. 340, 141–177 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Semrad, K., Green, R. & Schroeder, R. RNA chaperone activity of large ribosomal subunit proteins from Escherichia coli. RNA 10, 1855–1860 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Noller, H. F. The driving force for molecular evolution of translation. RNA 10, 1833–1837 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Takyar, S., Hickerson, R. P. & Noller, H. F. mRNA helicase activity of the ribosome. Cell 120, 49–58 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Gabashvili, I. S. et al. The polypeptide tunnel system in the ribosome and its gating in erythromycin resistance mutants of L4 and L22. Mol. Cell 8, 181–188 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Tenson, T. & Ehrenberg, M. Regulatory nascent peptides in the ribosomal tunnel. Cell 108, 591–594 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Berisio, R. et al. Structural insight into the role of the ribosomal tunnel in cellular regulation. Nature Struct. Biol. 10, 366–370 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Nakatogawa, H., Murakami, A. & Ito, K. Control of SecA and SecM translation by protein secretion. Curr. Opin. Microbiol. 7, 145–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Tu, D., Blaha, G., Moore, P. B. & Steitz, T. A. Structures of MLSBK antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance. Cell 121, 257–270 (2005). An important refinement in the use of Haloarcula subunits for antibiotic binding studies. Also sheds light on the mechanisms of nucleotide A2058 and r-protein L22 mutations in macrolide resistance.

    Article  CAS  PubMed  Google Scholar 

  43. Ferbitz, L. et al. Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature 431, 590–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Fourmy, D., Recht, M. I., Blanchard, S. C. & Puglisi, J. D. Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic. Science 274, 1367–1371 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Yoshizawa, S., Fourmy, D. & Puglisi, J. D. Structural origins of gentamicin antibiotic action. EMBO J. 17, 6437–6448 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carter, A. P. et al. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407, 340–348 (2000). References 16, 46 and 57 are examples of initial ground-breaking studies by three different research groups that revealed the molecular details of ribosomal subunits and antibiotic interactions. For all these studies, the readers are referred to the atomic coordinates in the databases ( Tables 2 and 3).

    Article  CAS  PubMed  Google Scholar 

  47. Vicens, Q. & Westhof, E. Crystal structure of paromomycin docked into the eubacterial ribosomal decoding A site. Structure (Camb.) 9, 647–658 (2001).

    Article  CAS  Google Scholar 

  48. Vicens, Q. & Westhof, E. Crystal structure of geneticin bound to a bacterial 16S ribosomal RNA A site oligonucleotide. J. Mol. Biol. 326, 1175–1188 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Hermann, T. Drugs targeting the ribosome. Curr. Opin. Struct. Biol. 15, 355–366 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Rodnina, M. V. et al. Thiostrepton inhibits the turnover but not the GTPase of elongation factor G on the ribosome. Proc. Natl Acad. Sci. USA 96, 9586–9590 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Brandi, L. et al. The translation initiation functions of IF2: targets for thiostrepton inhibition. J. Mol. Biol. 335, 881–894 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Bowen, W. S., Van Dyke, N., Murgola, E. J., Lodmell, J. S. & Hill, W. E. Interaction of thiostrepton and elongation factor-G with the ribosomal protein L11-binding domain. J. Biol. Chem. 280, 2934–2943 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. McNicholas, P. M. et al. Evernimicin binds exclusively to the 50S ribosomal subunit and inhibits translation in cell-free systems derived from both Gram-positive and Gram-negative bacteria. Antimicrob. Agents Chemother. 44, 1121–1126 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Belova, L., Tenson, T., Xiong, L., McNicholas, P. M. & Mankin, A. S. A novel site of antibiotic action in the ribosome: interaction of evernimicin with the large ribosomal subunit. Proc. Natl Acad. Sci. USA 98, 3726–3731 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kofoed, C. B. & Vester, B. Interaction of avilamycin with ribosomes and resistance caused by mutations in 23S rRNA. Antimicrob. Agents Chemother. 46, 3339–3342 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Treede, I. et al. The avilamycin resistance determinants AviRa and AviRb methylate 23S rRNA at the guanosine 2535 base and the uridine 2479 ribose. Mol. Microbiol. 49, 309–318 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Schlunzen, F. et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413, 814–821 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Hansen, J. L. et al. The structures of four macrolide antibiotics bound to the large ribosomal subunit. Mol. Cell 10, 117–128 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Hansen, J. L., Moore, P. B. & Steitz, T. A. Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit. J. Mol. Biol. 330, 1061–1075 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Harms, J. M., Schlunzen, F., Fucini, P., Bartels, H. & Yonath, A. Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin. BMC Biol. 2, 4 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Pringle, M., Poehlsgaard, J., Vester, B. & Long, K. S. Mutations in ribosomal protein L3 and 23S ribosomal RNA at the peptidyl transferase centre are associated with reduced susceptibility to tiamulin in Brachyspira spp. isolates. Mol. Microbiol. 54, 1295–1306 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Schlunzen, F., Pyetan, E., Fucini, P., Yonath, A. & Harms, J. M. Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin. Mol. Microbiol. 54, 1287–1294 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Kloss, P., Xiong, L., Shinabarger, D. L. & Mankin, A. S. Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center. J. Mol. Biol. 294, 93–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Thompson, J., O'Connor, M., Mills, J. A. & Dahlberg, A. E. The protein synthesis inhibitors, oxazolidinones and chloramphenicol, cause extensive translational inaccuracy in vivo. J. Mol. Biol. 322, 273–279 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Yoshizawa, S., Fourmy, D. & Puglisi, J. D. Recognition of the codon-anticodon helix by ribosomal RNA. Science 285, 1722–1725 (1999). First conclusive experimental data that link the 16S rRNA bases A1492 and A1493 with the decoding process.

    Article  CAS  PubMed  Google Scholar 

  66. Ogle, J. M. et al. Recognition of cognate transfer RNA by the 30S ribosomal subunit. Science 292, 897–902 (2001). Crystal study that confirms the involvement of A1492 and A1493 in the decoding process and links their movement with other conformational changes in the 30S ribosomal subunit. See also reference 67 for a review.

    Article  CAS  PubMed  Google Scholar 

  67. Ogle, J. M., Carter, A. P. & Ramakrishnan, V. Insights into the decoding mechanism from recent ribosome structures. Trends Biochem. Sci. 28, 259–266 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Piepenburg, O. et al. Intact aminoacyl-tRNA is required to trigger GTP hydrolysis by elongation factor Tu on the ribosome. Biochemistry 39, 1734–1738 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Cochella, L. & Green, R. An active role for tRNA in decoding beyond codon:anticodon pairing. Science 308, 1178–1180 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Pfister, P. et al. Mutagenesis of 16S rRNA C1409–G1491 base-pair differentiates between 6′-OH and 6′-NH3+ aminoglycosides. J. Mol. Biol. 346, 467–475 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Gregory, S. T., Carr, J. F. & Dahlberg, A. E. A mutation in the decoding center of Thermus thermophilus 16S rRNA suggests a novel mechanism of streptomycin resistance. J. Bacteriol. 187, 2200–2202 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thompson, J., Skeggs, P. A. & Cundliffe, E. Methylation of 16S ribosomal RNA and resistance to the aminoglycoside antibiotics gentamicin and kanamycin determined by DNA from the gentamicin-producer, Micromonospora purpurea. Mol. Gen. Genet. 201, 168–173 (1985).

    Article  CAS  PubMed  Google Scholar 

  74. Beauclerk, A. A. & Cundliffe, E. Sites of action of two ribosomal RNA methylases responsible for resistance to aminoglycosides. J. Mol. Biol. 193, 661–671 (1987).

    Article  CAS  PubMed  Google Scholar 

  75. Douthwaite, S., Fourmy, D. & Yoshizawa, S. in Fine-tuning of RNA Functions by Modification and Editing (ed. Grosjean, H.) 287–309 (Springer–Verlag, New York, 2005).

    Google Scholar 

  76. Gong, F. & Yanofsky, C. Instruction of translating ribosome by nascent peptide. Science 297, 1864–1867 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Weisblum, B. Erythromycin resistance by ribosome modification. Antimicrob. Agents Chemother. 39, 577–585 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cundliffe, E. in The Ribosome: Structure, Function and Evolution (eds Hill, W. E. et al.) 479–490 (American Society for Microbiology, Washington DC, 1990).

    Google Scholar 

  79. Bryskier, A. J., Butzler, J. P., Neu, H. C. & Tulkens, P. M. Macrolides: Chemistry, Pharmacology and Clinical Uses (Arnette Blackwell, Paris, 1993).

    Google Scholar 

  80. Schönfeld, W. & Kirst, H. A. (eds) Macrolide Antibiotics (Birkhäuser, Basel, 2002).

    Book  Google Scholar 

  81. Tenson, T., Lovmar, M. & Ehrenberg, M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J. Mol. Biol. 330, 1005–1014 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Weisblum, B. Insights into erythromycin action from studies of its activity as inducer of resistance. Antimicrob. Agents Chemother. 39, 797–805 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tenson, T. & Mankin, A. S. Short peptides conferring resistance to macrolide antibiotics. Peptides 22, 1661–1668 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Poulsen, S. M., Kofoed, C. & Vester, B. Inhibition of the ribosomal peptidyl transferase reaction by the mycarose moiety of the antibiotics carbomycin, spiramycin and tylosin. J. Mol. Biol. 304, 471–481 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Champney, W. S. Bacterial ribosomal subunit assembly is an antibiotic target. Curr. Top. Med. Chem. 3, 929–947 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Katz, L. & Ashley, G. W. Translation and protein synthesis: macrolides. Chem. Rev. 105, 499–528 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Bryskier, A. Ketolides — telithromycin, an example of a new class of antibacterial agents. Clin. Microbial. Infect. 6, 661–669 (2000).

    Article  CAS  Google Scholar 

  88. Farrell, D. J. & Felmingham, D. Activities of telithromycin against 13,874 Streptococcus pneumoniae isolates collected between 1999 and 2003. Antimicrob. Agents Chemother. 48, 1882–1884 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Schlunzen, F. et al. Structural basis for the antibiotic activity of ketolides and azalides. Structure (Camb.) 11, 329–338 (2003).

    Article  CAS  Google Scholar 

  90. Douthwaite, S. & Aagaard, C. Erythromycin binding is reduced in ribosomes with conformational alterations in the 23S rRNA peptidyl transferase loop. 232, 725–731 (1993).

  91. Yonath, A. & Bashan, A. Ribosomal crystallography: initiation, peptide bond formation, and amino acid polymerization are hampered by antibiotics. Annu. Rev. Microbiol. 58, 233–251 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Pfister, P. et al. 23S rRNA base pair 2057–2611 determines ketolide susceptibility and fitness cost of the macrolide resistance mutation 2058A to G. Proc. Natl Acad. Sci. USA 102, 5180–5185 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Awan, A., Brennan, R. J., Regan, A. C. & Barber, J. The conformations of the macrolide antibiotics erythromycin A, azithromycin and clarithromycin in aqueous solution: a H-1 NMR study. J. Chem. Soc. Perkin Trans. I 2, 1645–1652 (2000).

    Article  Google Scholar 

  94. Zalacain, M. & Cundliffe, E. Cloning of tlrD, a fourth resistance gene, from the tylosin producer, Streptomyces fradiae. Gene 97, 137–142 (1991).

    Article  CAS  PubMed  Google Scholar 

  95. Zalacain, M. & Cundliffe, E. Methylation of 23S rRNA caused by tlrA (ermSF), a tylosin resistance determinant from Streptomyces fradiae. J. Bacteriol. 171, 4254–4260 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu, M. & Douthwaite, S. Resistance to the macrolide antibiotic tylosin is conferred by single methylations at 23S rRNA nucleotides G748 and A2058 acting in synergy. Proc. Natl Acad. Sci. USA 99, 14658–14663 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Novotny, G. W., Jakobsen, L., Andersen, N. M., Poehlsgaard, J. & Douthwaite, S. Ketolide antimicrobial activity persists after disruption of interactions with domain II of 23S rRNA. Antimicrob. Agents Chemother. 48, 3677–3683 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Xiong, L., Shah, S., Mauvais, P. & Mankin, A. S. A ketolide resistance mutation in domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase centre. Mol. Microbiol. 31, 633–639 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Hansen, L. H., Mauvais, P. & Douthwaite, S. The macrolide-ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA. Mol. Microbiol. 31, 623–631 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Garza-Ramos, G., Xiong, L., Zhong, P. & Mankin, A. Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA. J. Bacteriol. 183, 6898–6907 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Xiong, L., Korkhin, Y. & Mankin, A. S. Binding site of the bridged macrolides in the Escherichia coli ribosome. Antimicrob. Agents Chemother. 49, 281–288 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Berisio, R. et al. Structural insight into the antibiotic action of telithromycin against resistant mutants. J. Bacteriol. 185, 4276–4279 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Vester, B. & Douthwaite, S. Macrolide resistance conferred by base substitutions in 23S rRNA. Antimicrob. Agents Chemother. 45, 1–12 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pfister, P. et al. The structural basis of macrolide-ribosome binding assessed using mutagenesis of 23S rRNA positions 2058 and 2059. J. Mol. Biol. 342, 1569–1581 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Wittmann, H. G. et al. Biochemical and genetic studies on two different types of erythromycin resistant mutants of Escherichia coli with altered ribosomal proteins. Mol. Gen. Genet. 127, 175–189 (1973).

    Article  CAS  PubMed  Google Scholar 

  106. Pardo, D. & Rosset, R. Properties of ribosomes from erythromycin resistant mutants of Escherichia coli. Mol. Gen. Genet. 156, 267–271 (1977).

    Article  CAS  PubMed  Google Scholar 

  107. Chittum, H. S. & Champney, W. S. Ribosomal protein gene sequence changes in erythromycin-resistant mutants of Escherichia coli. J. Bacteriol. 176, 6192–6198 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tait-Kamradt, A. et al. Mutations in 23S rRNA and ribosomal protein L4 account for resistance in pneumococcal strains selected in vitro by macrolide passage. Antimicrob. Agents Chemother. 44, 2118–2125 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Farrell, D. J., Morrissey, I., Bakker, S., Buckridge, S. & Felmingham, D. In vitro activities of telithromycin, linezolid, and quinupristin-dalfopristin against Streptococcus pneumoniae with macrolide resistance due to ribosomal mutations. Antimicrob. Agents Chemother. 48, 3169–3171 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gregory, S. T. & Dahlberg, A. E. Erythromycin resistance mutations in ribosomal proteins L22 and L4 perturb the higher order structure of 23 S ribosomal RNA. J. Mol. Biol. 289, 827–834 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Davydova, N., Streltsov, V., Wilce, M., Liljas, A. & Garber, M. L22 ribosomal protein and effect of its mutation on ribosome resistance to erythromycin. J. Mol. Biol. 322, 635–644 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Skinner, R., Cundliffe, E. & Schmidt, F. J. Site of action of a ribosomal RNA methylase responsible for resistance to erythromycin and other antibiotics. J. Biol. Chem. 258, 12702–12706 (1983).

    CAS  PubMed  Google Scholar 

  113. Roberts, M. C. Resistance to macrolide, lincosamide, streptogramin, ketolide, and oxazolidinone antibiotics. Mol. Biotechnol. 28, 47–62 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Liu, M. & Douthwaite, S. Activity of the ketolide telithromycin is refractory to Erm monomethylation of bacterial rRNA. Antimicrob. Agents Chemother. 46, 1629–1633 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sutcliffe, J. A. & Leclercq, R. in Macrolide Antibiotics (eds Schönfeld, W. & Kirst, H. A.) 281–317 (Birkhäuser, Berlin, 2002).

    Book  Google Scholar 

  116. Douthwaite, S., Crain, P. F., Liu, M. & Poehlsgaard, J. The tylosin-resistance methyltransferase RlmAII (TlrB) modifies the N-1 position of 23S rRNA nucleotide G748. J. Mol. Biol. 337, 1073–1077 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Abbanat, D. et al. In vitro activities of novel 2-fluoro-naphthyridine-containing ketolides. Antimicrob. Agents Chemother. 49, 309–315 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Poehlsgaard, J. & Douthwaite, S. The macrolide binding site on the bacterial ribosome. Curr. Drug Targets Infect. Disord. 2, 67–78 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Brodersen, D. E. et al. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103, 1143–1154 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Vicens, Q. & Westhof, E. Crystal structure of a complex between the aminoglycoside tobramycin and an oligonucleotide containing the ribosomal decoding a site. Chem. Biol. 9, 747–755 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Han, Q. et al. Molecular recognition by glycoside pseudo base pairs and triples in an apramycin–RNA complex. Angew. Chem. (Int. Ed. Engl.) 44, 2694–2700 (2005).

    Article  CAS  Google Scholar 

  122. Pioletti, M. et al. Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J. 20, 1829–1839 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sutcliffe, J. Rib-X Pharmaceuticals. Antibiotics Conference, Tartu, Estonia, June 2005.

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Acknowledgements

Support from the Danish Research Agency and the Nucleic Acid Center of the Danish Grundforskningsfond are gratefully acknowledged.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, University of Southern Denmark, Odense M, DK-5230, Denmark

    Jacob Poehlsgaard & Stephen Douthwaite

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  1. Jacob Poehlsgaard
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Correspondence to Stephen Douthwaite.

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DATABASES

Entrez

Deinococcus radiodurans

Escherichia coli

Haloarcula marismortui

Thermus thermophilus

FURTHER INFORMATION

Stephen Douthwaite's laboratory

The Protein Data Bank

Glossary

HAIRPIN

A structural element that makes a 180° turn and doubles back on itself; in proteins, normally formed from a β-strand.

POLYKETIDES

Secondary metabolites that are biosynthesized in a stepwise manner from simple 2-, 3- and 4-carbon building blocks; can have antimicrobial, antifungal, antiparasitic, antitumour or agrochemical properties.

MACROLACTONE RING

The cyclic ester ring at the core of macrolide antibiotics.

MACROLIDE 5-AMINO SUGAR

The nitrogen-containing sugar directly attached to the 5-carbon of the macrolactone ring (desosamine in erythromycin and mycaminose in tylosin).

ELECTROSTATIC INTERACTIONS

Interactions between charged molecules or atoms.

HYDROPHOBIC INTERACTIONS

Interactions that rely on the tendency of non-polar groups to aggregate to avoid contact with a polar solvent.

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Poehlsgaard, J., Douthwaite, S. The bacterial ribosome as a target for antibiotics. Nat Rev Microbiol 3, 870–881 (2005). https://doi.org/10.1038/nrmicro1265

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