Ribosome Protection Proteins: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Yong-gui Gao.

Ribosome is one of the most conserved and sophisticated macromolecular machines that carries out the essential process of protein synthesis in cells. Given the essential function of ribosome as well as difference of bacterial and eukaryotic ribosome, it has been an active target for over half clinically used antibiotics.

  • antibiotic resistance
  • ribosome protection
  • ABC-F proteins
  • peptidyl transferase center
  • nascent peptide exit tunnel
Please wait, diff process is still running!

References

  1. Rodnina, M.V.; Beringer, M.; Wintermeyer, W. Mechanism of peptide bond formation on the ribosome. Q. Rev. Biophys. 2006, 39, 203–225.
  2. Arenz, S.; Wilson, D.N. Bacterial Protein Synthesis as a Target for Antibiotic Inhibition. Cold Spring Harb. Perspect. Med. 2016, 6.
  3. Wilson, D.N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat. Rev. Microbiol. 2014, 12, 35–48.
  4. Poehlsgaard, J.; Douthwaite, S. The bacterial ribosome as a target for antibiotics. Nat. Rev. Microbiol. 2005, 3, 870–881.
  5. Durand, G.A.; Raoult, D.; Dubourg, G. Antibiotic discovery: History, methods and perspectives. Int. J. Antimicrob. Agents 2019, 53, 371–382.
  6. Forsberg, K.J.; Reyes, A.; Wang, B.; Selleck, E.M.; Sommer, M.O.; Dantas, G. The shared antibiotic resistome of soil bacteria and human pathogens. Science 2012, 337, 1107–1111.
  7. World Health Organization. Critically Important Antimicrobials for Human Medicine: Ranking of Antimicrobial Agents for Risk Management of Antimicrobial Resistance Due to Non-Human Use. 2019. Available online: (accessed on 15 March 2021).
  8. World Health Organization. Model List of Essential Medicines. 2019. Available online: (accessed on 15 March 2021).
  9. Vázquez-Laslop, N.; Mankin, A.S. How Macrolide Antibiotics Work. Trends Biochem. Sci. 2018, 43, 668–684.
  10. Sothiselvam, S.; Neuner, S.; Rigger, L.; Klepacki, D.; Micura, R.; Vázquez-Laslop, N.; Mankin, A.S. Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size. Cell Rep. 2016, 16, 1789–1799.
  11. Jiang, M.; Karasawa, T.; Steyger, P.S. Aminoglycoside-Induced Cochleotoxicity: A Review. Front Cell Neurosci. 2017, 11, 308.
  12. Choi, J.; Marks, J.; Zhang, J.; Chen, D.H.; Wang, J.; Vázquez-Laslop, N.; Mankin, A.S.; Puglisi, J.D. Dynamics of the context-specific translation arrest by chloramphenicol and linezolid. Nat Chem. Biol. 2020, 16, 310–317.
  13. Marks, J.; Kannan, K.; Roncase, E.J.; Klepacki, D.; Kefi, A.; Orelle, C.; Vázquez-Laslop, N.; Mankin, A.S. Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center. Proc. Natl. Acad. Sci. USA 2016, 113, 12150–12155.
  14. 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 2005, 121, 257–270.
  15. Schlünzen, F.; Zarivach, R.; Harms, J.; Bashan, A.; Tocilj, A.; Albrecht, R.; Yonath, A.; Franceschi, F. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 2001, 413, 814–821.
  16. Gao, Y.G.; Selmer, M.; Dunham, C.M.; Weixlbaumer, A.; Kelley, A.C.; Ramakrishnan, V. The structure of the ribosome with elongation factor G trapped in the posttranslocational state. Science 2009, 326, 694–699.
  17. Seo, H.S.; Abedin, S.; Kamp, D.; Wilson, D.N.; Nierhaus, K.H.; Cooperman, B.S. EF-G-dependent GTPase on the ribosome. conformational change and fusidic acid inhibition. Biochemistry 2006, 45, 2504–2514.
  18. Wilson, D.N.; Hauryliuk, V.; Atkinson, G.C.; O’Neill, A.J. Target protection as a key antibiotic resistance mechanism. Nat. Rev. Microbiol. 2020, 18, 637–648.
  19. Meydan, S.; Marks, J.; Klepacki, D.; Sharma, V.; Baranov, P.V.; Firth, A.E.; Margus, T.; Kefi, A.; Vázquez-Laslop, N.; Mankin, A.S. Retapamulin-Assisted Ribosome Profiling Reveals the Alternative Bacterial Proteome. Mol. Cell 2019, 74, 481.e6–493.e6.
  20. Paukner, S.; Riedl, R. Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance. Cold Spring Harb. Perspect. Med. 2017, 7.
  21. Lin, J.; Zhou, D.; Steitz, T.A.; Polikanov, Y.S.; Gagnon, M.G. Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design. Annu. Rev. Biochem. 2018, 87, 451–478.
  22. Peterson, E.; Kaur, P. Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens. Front. Microbiol. 2018, 9, 2928.
  23. Witzky, A.; Tollerson, R.; Ibba, M. Translational control of antibiotic resistance. Open Biol. 2019, 9, 190051.
  24. Ramu, H.; Mankin, A.; Vazquez-Laslop, N. Programmed drug-dependent ribosome stalling. Mol. Microbiol. 2009, 71, 811–824.
  25. Grossman, T.H. Tetracycline Antibiotics and Resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a025387.
  26. Nguyen, F.; Starosta, A.L.; Arenz, S.; Sohmen, D.; Dönhöfer, A.; Wilson, D.N. Tetracycline antibiotics and resistance mechanisms. Biol. Chem. 2014, 395, 559–575.
  27. Jenner, L.; Starosta, A.L.; Terry, D.S.; Mikolajka, A.; Filonava, L.; Yusupov, M.; Blanchard, S.C.; Wilson, D.N.; Yusupova, G. Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis. Proc. Natl. Acad. Sci. USA 2013, 110, 3812–3816.
  28. Burdett, V. Purification and characterization of Tet(M), a protein that renders ribosomes resistant to tetracycline. J. Biol. Chem. 1991, 266, 2872–2877.
  29. CARD 2020. The Comprehensive Antibiotic Resistance Database. Available online: (accessed on 15 March 2021).
  30. Warburton, P.J.; Amodeo, N.; Roberts, A.P. Mosaic tetracycline resistance genes encoding ribosomal protection proteins. J. Antimicrob. Chemother. 2016, 71, 3333–3339.
  31. Connell, S.R.; Trieber, C.A.; Dinos, G.P.; Einfeldt, E.; Taylor, D.E.; Nierhaus, K.H. Mechanism of Tet(O)-mediated tetracycline resistance. EMBO J. 2003, 22, 945–953.
  32. Connell, S.R.; Tracz, D.M.; Nierhaus, K.H.; Taylor, D.E. Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrob. Agents Chemother. 2003, 47, 3675–3681.
  33. Dönhöfer, A.; Franckenberg, S.; Wickles, S.; Berninghausen, O.; Beckmann, R.; Wilson, D.N. Structural basis for TetM-mediated tetracycline resistance. Proc. Natl. Acad. Sci. USA 2012, 109, 16900–16905.
  34. 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. Mechanism of tetracycline resistance by ribosomal protection protein Tet(O). Nat. Commun. 2013, 4, 1477.
  35. Arenz, S.; Nguyen, F.; Beckmann, R.; Wilson, D.N. Cryo-EM structure of the tetracycline resistance protein TetM in complex with a translating ribosome at 3.9-Å resolution. Proc. Natl. Acad. Sci. USA 2015, 112, 5401–5406.
  36. Schedlbauer, A.; Kaminishi, T.; Ochoa-Lizarralde, B.; Dhimole, N.; Zhou, S.; López-Alonso, J.P.; Connell, S.R.; Fucini, P. Structural characterization of an alternative mode of tigecycline binding to the bacterial ribosome. Antimicrob. Agents Chemother. 2015, 59, 2849–2854.
  37. Olson, M.W.; Ruzin, A.; Feyfant, E.; Rush, T.S.; O’Connell, J.; Bradford, P.A. Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob. Agents Chemother. 2006, 50, 2156–2166.
  38. Beabout, K.; Hammerstrom, T.G.; Wang, T.T.; Bhatty, M.; Christie, P.J.; Saxer, G.; Shamoo, Y. Rampant Parasexuality Evolves in a Hospital Pathogen during Antibiotic Selection. Mol. Biol. Evol. 2015, 32, 2585–2597.
  39. McLaws, F.B.; Larsen, A.R.; Skov, R.L.; Chopra, I.; O’Neill, A.J. Distribution of fusidic acid resistance determinants in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2011, 55, 1173–1176.
  40. Tomlinson, J.H.; Kalverda, A.P.; Calabrese, A.N. Fusidic acid resistance through changes in the dynamics of the drug target. Proc. Natl. Acad. Sci. USA 2020, 117, 25523–25531.
  41. Tomlinson, J.H.; Thompson, G.S.; Kalverda, A.P.; Zhuravleva, A.; O’Neill, A.J. A target-protection mechanism of antibiotic resistance at atomic resolution: Insights into FusB-type fusidic acid resistance. Sci. Rep. 2016, 6, 19524.
  42. O’Neill, A.J.; Chopra, I. Molecular basis of fusB-mediated resistance to fusidic acid in Staphylococcus aureus. Mol. Microbiol. 2006, 59, 664–676.
  43. Borg, A.; Pavlov, M.; Ehrenberg, M. Mechanism of fusidic acid inhibition of RRF- and EF-G-dependent splitting of the bacterial post-termination ribosome. Nucleic Acids Res. 2016, 44, 3264–3275.
  44. Cox, G.; Thompson, G.S.; Jenkins, H.T.; Peske, F.; Savelsbergh, A.; Rodnina, M.V.; Wintermeyer, W.; Homans, S.W.; Edwards, T.A.; O’Neill, A.J. Ribosome clearance by FusB-type proteins mediates resistance to the antibiotic fusidic acid. Proc. Natl. Acad. Sci. USA 2012, 109, 2102–2107.
  45. Guo, X.; Peisker, K.; Bäckbro, K.; Chen, Y.; Koripella, R.K.; Mandava, C.S.; Sanyal, S.; Selmer, M. Structure and function of FusB: An elongation factor G-binding fusidic acid resistance protein active in ribosomal translocation and recycling. Open Biol. 2012, 2, 120016.
  46. Sharkey, L.K.; Edwards, T.A.; O’Neill, A.J. ABC-F Proteins Mediate Antibiotic Resistance through Ribosomal Protection. mBio 2016, 7, e01975.
  47. Lenart, J.; Vimberg, V.; Vesela, L.; Janata, J.; Balikova Novotna, G. Detailed mutational analysis of Vga(A) interdomain linker: Implication for antibiotic resistance specificity and mechanism. Antimicrob. Agents Chemother. 2015, 59, 1360–1364.
  48. Sharkey, L.K.R.; O’Neill, A.J. Antibiotic Resistance ABC-F Proteins: Bringing Target Protection into the Limelight. ACS Infect. Dis. 2018, 4, 239–246.
  49. Ero, R.; Kumar, V.; Su, W.; Gao, Y.G. Ribosome protection by ABC-F proteins—Molecular mechanism and potential drug design. Protein Sci. 2019, 28, 684–693.
  50. Fostier, C.R.; Monlezun, L.; Ousalem, F.; Singh, S.; Hunt, J.F.; Boël, G. ABC-F translation factors: From antibiotic resistance to immune response. FEBS Lett. 2021, 595, 675–706.
  51. Murina, V.; Kasari, M.; Takada, H.; Hinnu, M.; Saha, C.K.; Grimshaw, J.W.; Seki, T.; Reith, M.; Putrinš, M.; Tenson, T.; et al. ABCF ATPases Involved in Protein Synthesis, Ribosome Assembly and Antibiotic Resistance: Structural and Functional Diversification across the Tree of Life. J. Mol. Biol. 2019, 431, 3568–3590.
  52. Ousalem, F.; Singh, S.; Chesneau, O.; Hunt, J.F.; Boël, G. ABC-F proteins in mRNA translation and antibiotic resistance. Res. Microbiol. 2019, 170, 435–447.
  53. He, T.; Shen, Y.; Schwarz, S.; Cai, J.; Lv, Y.; Li, J.; Feßler, A.T.; Zhang, R.; Wu, C.; Shen, J.; et al. Genetic environment of the transferable oxazolidinone/phenicol resistance gene optrA in Enterococcus faecalis isolates of human and animal origin. J. Antimicrob. Chemother. 2016, 71, 1466–1473.
  54. Hao, W.; Shan, X.; Li, D.; Schwarz, S.; Zhang, S.M.; Li, X.S.; Du, X.D. Analysis of a poxtA- and optrA-co-carrying conjugative multiresistance plasmid from Enterococcus faecalis. J. Antimicrob. Chemother. 2019, 74, 1771–1775.
  55. Sadowy, E. Linezolid resistance genes and genetic elements enhancing their dissemination in enterococci and streptococci. Plasmid 2018, 99, 89–98.
  56. Antonelli, A.; D’Andrea, M.M.; Brenciani, A.; Galeotti, C.L.; Morroni, G.; Pollini, S.; Varaldo, P.E.; Rossolini, G.M. Characterization of poxtA, a novel phenicol-oxazolidinone-tetracycline resistance gene from an MRSA of clinical origin. J. Antimicrob. Chemother. 2018, 73, 1763–1769.
  57. Wang, Y.; Lv, Y.; Cai, J.; Schwarz, S.; Cui, L.; Hu, Z.; Zhang, R.; Li, J.; Zhao, Q.; He, T.; et al. A novel gene, optrA, that confers transferable resistance to oxazolidinones and phenicols and its presence in Enterococcus faecalis and Enterococcus faecium of human and animal origin. J. Antimicrob. Chemother. 2015, 70, 2182–2190.
  58. Miyoshi-Akiyama, T.; Tada, T.; Ohmagari, N.; Viet Hung, N.; Tharavichitkul, P.; Pokhrel, B.M.; Gniadkowski, M.; Shimojima, M.; Kirikae, T. Emergence and Spread of Epidemic Multidrug-Resistant Pseudomonas aeruginosa. Genome Biol. Evol. 2017, 9, 3238–3245.
  59. World Health Organization. Prioritization of Pathogens to Guide Discovery, Research and Development of New Antibiotics for Drug Resistant Bacterial Infections, Including Tuberculosis. 2017. Available online: (accessed on 15 March 2021).
  60. Pereyre, S.; Goret, J.; Bébéar, C. Mycoplasma pneumoniae: Current Knowledge on Macrolide Resistance and Treatment. Front. Microbiol. 2016, 7, 974.
  61. Chen, Q.; Lu, W.; Zhou, D.; Zheng, G.; Liu, H.; Qian, C.; Zhou, W.; Lu, J.; Ni, L.; Bao, Q.; et al. Characterization of Two Macrolide Resistance-Related Genes in Multidrug-Resistant Pseudomonas Aeruginosa Isolates. Pol. J. Microbiol. 2020, 69, 349–356.
  62. Schroeder, M.R.; Stephens, D.S. Macrolide Resistance in Streptococcus pneumoniae. Front. Cell Infect. Microbiol. 2016, 6, 98.
  63. Gentry, D.R.; McCloskey, L.; Gwynn, M.N.; Rittenhouse, S.F.; Scangarella, N.; Shawar, R.; Holmes, D.J. Genetic characterization of Vga ABC proteins conferring reduced susceptibility to pleuromutilins in Staphylococcus aureus. Antimicrob. Agents Chemother. 2008, 52, 4507–4509.
  64. Vimberg, V.; Cavanagh, J.P.; Novotna, M.; Lenart, J.; Nguyen Thi Ngoc, B.; Vesela, J.; Pain, M.; Koberska, M.; Balikova Novotna, G. Ribosome-Mediated Attenuation of vga(A) Expression Is Shaped by the Antibiotic Resistance Specificity of Vga(A) Protein Variants. Antimicrob. Agents Chemother. 2020, 64.
  65. Lopes, E.; Conceição, T.; Poirel, L.; de Lencastre, H.; Aires-de-Sousa, M. Epidemiology and antimicrobial resistance of methicillin-resistant Staphylococcus aureus isolates colonizing pigs with different exposure to antibiotics. PLoS ONE 2019, 14, e0225497.
  66. Fan, R.; Li, D.; Feßler, A.T.; Wu, C.; Schwarz, S.; Wang, Y. Distribution of optrA and cfr in florfenicol-resistant Staphylococcus sciuri of pig origin. Vet. Microbiol. 2017, 210, 43–48.
  67. Su, W.; Kumar, V.; Ding, Y.; Ero, R.; Serra, A.; Lee, B.S.T.; Wong, A.S.W.; Shi, J.; Sze, S.K.; Yang, L.; et al. Ribosome protection by antibiotic resistance ATP-binding cassette protein. Proc. Natl. Acad. Sci. USA 2018, 115, 5157–5162.
  68. Crowe-McAuliffe, C.; Graf, M.; Huter, P.; Takada, H.; Abdelshahid, M.; Nováček, J.; Murina, V.; Atkinson, G.C.; Hauryliuk, V.; Wilson, D.N. Structural basis for antibiotic resistance mediated by the Bacillus subtilis ABCF ATPase VmlR. Proc. Natl. Acad. Sci. USA 2018, 115, 8978–8983.
  69. Murina, V.; Kasari, M.; Hauryliuk, V.; Atkinson, G.C. Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest. Nucleic Acids Res. 2018, 46, 3753–3763.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Feedback