Throwing a spanner in the works: antibiotics and the translation apparatus

The protein synthetic machinery is essential to all living cells and is one of the major targets for antibiotics. Knowledge of the structure and function of the ribosome and its associated factors is key to understanding the mechanism of drug action. Conversely, drugs have been used as tools to probe the translation cycle, thus providing a means to further our understanding of the steps that lead to protein synthesis. Our current understanding as to how antibiotics disrupt this process is reviewed here, with particular emphasis on the prokaryotic elongation cycle and those drugs that interact with ribosomal RNAs.

[1]  R. Amils,et al.  Location of the streptomycin ribosomal binding site explains its pleiotropic effects on protein biosynthesis. , 1994, Journal of Molecular Biology.

[2]  R. Brimacombe,et al.  A detailed model of the three-dimensional structure of Escherichia coli 16 S ribosomal RNA in situ in the 30 S subunit. , 1988, Journal of molecular biology.

[3]  A. Parmeggiani,et al.  Mechanism of action of kirromycin-like antibiotics. , 1985, Annual review of microbiology.

[4]  J. Menninger,et al.  Lincosamide antibiotics stimulate dissociation of peptidyl-tRNA from ribosomes , 1993, Antimicrobial Agents and Chemotherapy.

[5]  R. Gutell,et al.  Genetic and comparative analyses reveal an alternative secondary structure in the region of nt 912 of Escherichia coli 16S rRNA. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[6]  H. Noller,et al.  Interaction of elongation factors EF-G and EF-Tu with a conserved loop in 23S RNA , 1988, Nature.

[7]  V. Ramakrishnan,et al.  The structure of ribosomal protein S5 reveals sites of interaction with 16S rRNA , 1992, Nature.

[8]  K. Nierhaus,et al.  The inhibition pattern of antibiotics on the extent and accuracy of tRNA binding to the ribosome, and their effect on the subsequent steps in chain elongation. , 2005, European journal of biochemistry.

[9]  C. Spahn,et al.  Interaction of tRNAs with the ribosome at the A and P sites. , 1995, The EMBO journal.

[10]  L. Brakier-Gingras,et al.  Cross-linking of streptomycin to the 16S ribosomal RNA of Escherichia coli. , 1987, Biochemistry.

[11]  W. S. Champney,et al.  Ribosomal protein gene sequence changes in erythromycin-resistant mutants of Escherichia coli , 1994, Journal of bacteriology.

[12]  R. Buckingham,et al.  Mutant ribosomes can generate dominant kirromycin resistance , 1991, Journal of bacteriology.

[13]  K. Nierhaus,et al.  Characterisation of the binding of virginiamycin S to Escherichia coli ribosomes. , 1978, European journal of biochemistry.

[14]  A. Liljas,et al.  Three‐dimensional structure of the ribosomal translocase: elongation factor G from Thermus thermophilus. , 1994, The EMBO journal.

[15]  L. Bosch,et al.  Pulvomycin‐resistant mutants of E.coli elongation factor Tu. , 1994, The EMBO journal.

[16]  J. Davies,et al.  Antibiotic inhibition of group I ribozyme function , 1991, Nature.

[17]  V. Erdmann,et al.  Phosphorylation of Elongation Factor Tu Prevents Ternary Complex Formation (*) , 1995, The Journal of Biological Chemistry.

[18]  Harry F. Noller,et al.  Intermediate states in the movement of transfer RNA in the ribosome , 1989, Nature.

[19]  R. Wagner,et al.  E. coli ribosomes with a C912 to U base change in the 16S rRNA are streptomycin resistant. , 1986, The EMBO journal.

[20]  Y Endo,et al.  Ribotoxin recognition of ribosomal RNA and a proposal for the mechanism of translocation. , 1992, Trends in biochemical sciences.

[21]  J. Thompson,et al.  The binding of thiostrepton to 23S ribosomal RNA. , 1991, Biochimie.

[22]  J. Wang,et al.  The crystal structure of elongation factor G complexed with GDP, at 2.7 A resolution. , 1994, The EMBO journal.

[23]  J. Ballesta,et al.  Reaction of some macrolide antibiotics with the ribosome. Labeling of the binding site components. , 1986, Biochemistry.

[24]  S Thirup,et al.  Crystal Structure of the Ternary Complex of Phe-tRNAPhe, EF-Tu, and a GTP Analog , 1995, Science.

[25]  D. Hughes,et al.  Fusidic acid-resistant mutants define three regions in elongation factor G of Salmonella typhimurium. , 1994, Gene.

[26]  T. Yamada,et al.  Resistance to viomycin conferred by RNA of either ribosomal subunit , 1978, Nature.

[27]  K. Nierhaus,et al.  Solution of the ribosome riddle: how the ribosome selects the correct aminoacyl‐tRNA out of 41 similar contestants , 1993, Molecular microbiology.

[28]  R. Garrett,et al.  The importance of highly conserved nucleotides in the binding region of chloramphenicol at the peptidyl transfer centre of Escherichia coli 23S ribosomal RNA. , 1988, The EMBO journal.

[29]  H. Noller,et al.  Mutations in 16S ribosomal RNA disrupt antibiotic–RNA interactions. , 1989, The EMBO journal.

[30]  D. Assmann,et al.  Pulvomycin, an inhibitor of protein biosynthesis preventing ternary complex formation between elongation factor Tu, GTP, and aminoacyl-tRNA. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Harry F. Noller,et al.  Interaction of antibiotics with functional sites in 16S ribosomal RNA , 1987, Nature.

[32]  A. Yonath Approaching atomic resolution in crystallography of ribosomes. , 1992, Annual review of biophysics and biomolecular structure.

[33]  M. Cousin,et al.  Paromomycin and dihydrostreptomycin binding to Escherichia coli ribosomes. , 1976, European journal of biochemistry.

[34]  L. Brakier-Gingras,et al.  Mutations in the 915 region of Escherichia coli 16S ribosomal RNA reduce the binding of streptomycin to the ribosome. , 1991, Nucleic acids research.

[35]  S. Stern,et al.  Interactions of a small RNA with antibiotic and RNA ligands of the 30S subunit , 1994, Nature.

[36]  H. Noller,et al.  Interaction of tRNA with 23S rRNA in the ribosomal A, P, and E sites , 1989, Cell.

[37]  J. Ballesta,et al.  Protein components of the erythromycin binding site in bacterial ribosomes. , 1988, The Journal of biological chemistry.

[38]  H. Rheinberger,et al.  Partial release of AcPhe-Phe-tRNA from ribosomes during poly(U)-dependent poly(Phe) synthesis and the effects of chloramphenicol. , 1990, European journal of biochemistry.

[39]  P. Mitchell,et al.  Selective isolation and detailed analysis of intra-RNA cross-links induced in the large ribosomal subunit of E. coli: a model for the tertiary structure of the tRNA binding domain in 23S RNA. , 1990, Nucleic acids research.

[40]  D. Colthurst,et al.  Fragmentation of the ribosome to investigate RNA-ligand interactions. , 1995, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[41]  H. Noller,et al.  Chloramphenicol, erythromycin, carbomycin and vernamycin B protect overlapping sites in the peptidyl transferase region of 23S ribosomal RNA. , 1987, Biochimie.

[42]  U. Johanson,et al.  A new mutation in 16S rRNA of Escherichia coli conferring spectinomycin resistance. , 1995, Nucleic acids research.

[43]  A. P. Potapov,et al.  Synergism between the GTPase activities of EF-Tu.GTP and EF-G.GTP on empty ribosomes. Elongation factors as stimulators of the ribosomal oscillation between two conformations. , 1994, Journal of molecular biology.

[44]  J. Bodley,et al.  Translocation. XV. Characteristics of and structural requirements for the interaction of 24,25-dihydrofusidic acid with ribosome.elongation factor G complexes , 1975 .

[45]  J A Langer,et al.  A complete mapping of the proteins in the small ribosomal subunit of Escherichia coli. , 1987, Science.

[46]  L. Bosch,et al.  The structural and functional basis for the kirromycin resistance of mutant EF‐Tu species in Escherichia coli. , 1994, The EMBO journal.

[47]  L. Brakier-Gingras,et al.  The 5′ proximal helix of 16S rRNA is involved in the binding of streptomycin to the ribosome , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  H. Noller,et al.  A single base substitution in 16S ribosomal RNA suppresses streptomycin dependence and increases the frequency of translational errors , 1991, Cell.

[49]  O. W. Odom,et al.  The Movement of tRNA through Ribosomes during Peptide Elongation: The Displacement Reaction Model , 1986 .

[50]  Chris M. Brown,et al.  Translational termination: "stop" for protein synthesis or "pause" for regulation of gene expression. , 1992, Biochemistry.

[51]  E. Blackburn,et al.  The nucleotide sequence of the 17S ribosomal RNA gene of Tetrahymena thermophila and the identification of point mutations resulting in resistance to the antibiotics paromomycin and hygromycin. , 1985, The Journal of biological chemistry.

[52]  O. Bischof,et al.  Analysis of the puromycin binding site in the 70 S ribosome of Escherichia coli at the peptide level. , 1994, The Journal of biological chemistry.

[53]  H. Noller Ribosomal RNA and translation. , 1991, Annual review of biochemistry.

[54]  B. Clark,et al.  Cross-linking of tRNA at two different sites of the elongation factor Tu. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[55]  A. Dahlberg,et al.  Effects of mutagenesis of a conserved base-paired site near the decoding region of Escherichia coli 16 S ribosomal RNA. , 1990, Journal of molecular biology.

[56]  Sven-Erik Skold Chemical crosslinking of elongation factor G to the 23S RNA in 70S ribosomes from Escherichia coli , 1983 .

[57]  P. Vannuffel,et al.  The role of rRNA bases in the interaction of peptidyltransferase inhibitors with bacterial ribosomes. , 1992, The Journal of biological chemistry.

[58]  J. Thompson,et al.  Replacement of the L11 binding region within E.coli 23S ribosomal RNA with its homologue from yeast: in vivo and in vitro analysis of hybrid ribosomes altered in the GTPase centre. , 1993, The EMBO journal.

[59]  H. Noller,et al.  Independent in vitro assembly of a ribonucleoprotein particle containing the 3' domain of 16S rRNA. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[60]  M. Brink,et al.  Spectinomycin interacts specifically with the residues G1064 and C1192 in 16S rRNA, thereby potentially freezing this molecule into an inactive conformation. , 1994, Nucleic Acids Research.

[61]  R. Garrett,et al.  Characterization of the binding sites of protein L11 and the L10.(L12)4 pentameric complex in the GTPase domain of 23 S ribosomal RNA from Escherichia coli. , 1990, Journal of molecular biology.

[62]  R. Brimacombe Structure-function correlations (and discrepancies) in the 16S ribosomal RNA from Escherichia coli. , 1992, Biochimie.

[63]  A. E. Dahlberg,et al.  Spectinomycin resistance at site 1192 in 16S ribosomal RNA of E. coli: an analysis of three mutants. , 1987, Biochimie.

[64]  J. Bodley,et al.  Alpha-sarcin cleavage of ribosomal RNA is inhibited by the binding of elongation factor G or thiostrepton to the ribosome. , 1991, Nucleic acids research.

[65]  K. Nierhaus,et al.  Identification of the chloramphenicol-binding protein in Escherichia coli ribosomes by partial reconstitution. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[66]  R. Garrett,et al.  Antibiotic interactions at the GTPase‐associated centre within Escherichia coli 23S rRNA. , 1989, The EMBO journal.

[67]  R. Garrett,et al.  Cross-hypersensitivity effects of mutations in 23 S rRNA yield insight into aminoacyl-tRNA binding. , 1994, Journal of molecular biology.

[68]  P. Vannuffel,et al.  Chemical probing of a virginiamycin M-promoted conformational change of the peptidyl-transferase domain. , 1994, Nucleic acids research.

[69]  J. Bodley,et al.  Some characteristics of and structural requirements for the interaction of 24,25-dihydrofusidic acid with ribosome - elongation factor g Complexes. , 1975, Biochemistry.

[70]  H. Noller,et al.  Unusual resistance of peptidyl transferase to protein extraction procedures. , 1992, Science.

[71]  K. Nierhaus,et al.  Viomycin favours the formation of 70S ribosome couples , 1978, Molecular and General Genetics MGG.

[72]  S. Douthwaite Interaction of the antibiotics clindamycin and lincomycin with Escherichia coli 23S ribosomal RNA. , 1992, Nucleic acids research.

[73]  D. Otto,et al.  Erythromycin, carbomycin, and spiramycin inhibit protein synthesis by stimulating the dissociation of peptidyl-tRNA from ribosomes , 1982, Antimicrobial Agents and Chemotherapy.

[74]  H. Noller,et al.  RNA-protein interactions in 30S ribosomal subunits: folding and function of 16S rRNA. , 1989, Science.

[75]  K. Nierhaus,et al.  Evidence that the G2661 region of 23S rRNA is located at the ribosomal binding sites of both elongation factors. , 1987, Biochimie.

[76]  H. Noller,et al.  Mutations in ribosomal proteins S4 and S12 influence the higher order structure of 16 S ribosomal RNA. , 1989, Journal of molecular biology.

[77]  J. Remme,et al.  Novel mutants of 23S RNA: characterization of functional properties. , 1992, Nucleic acids research.

[78]  E. Cundliffe,et al.  Sites of action of two ribosomal RNA methylases responsible for resistance to aminoglycosides. , 1987, Journal of molecular biology.

[79]  R P May,et al.  Inter‐protein distances within the large subunit from Escherichia coli ribosomes. , 1992, The EMBO journal.

[80]  I. Wool,et al.  The conformation of the sarcin/ricin loop from 28S ribosomal RNA. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[81]  Genetic position and amino acid replacements of several mutations in ribosomal protein S5 from Escherichia coli , 1975, Molecular and General Genetics MGG.

[82]  H. Noller,et al.  Selective perturbation of G530 of 16 S rRNA by translational miscoding agents and a streptomycin-dependence mutation in protein S12. , 1994, Journal of molecular biology.

[83]  R. Gutell,et al.  A compilation of large subunit (23S and 23S-like) ribosomal RNA structures: 1993. , 1992, Nucleic acids research.

[84]  U. Kutay,et al.  Similarities and differences in the inhibition patterns of thiostrepton and viomycin: evidence for two functionally different populations of P sites when occupied with AcPhe-tRNA. , 1990, Biochimica et biophysica acta.

[85]  Ernest Frederick Gale,et al.  The Molecular basis of antibiotic action , 1972 .

[86]  H. Urlaub,et al.  Protein‐rRNA binding features and their structural and functional implications in ribosomes as determined by cross‐linking studies. , 1995, The EMBO journal.

[87]  J. Thompson,et al.  Site-directed mutagenesis of Escherichia coli 23 S ribosomal RNA at position 1067 within the GTP hydrolysis centre. , 1988, Journal of molecular biology.

[88]  U. Geigenmüller,et al.  The allosteric three-site model for the ribosomal elongation cycle. New insights into the inhibition mechanisms of aminoglycosides, thiostrepton, and viomycin. , 1988, The Journal of biological chemistry.

[89]  F. Franceschi,et al.  Ribosomal proteins L15 and L16 are mere late assembly proteins of the large ribosomal subunit. Analysis of an Escherichia coli mutant lacking L15. , 1990, The Journal of biological chemistry.

[90]  M. O'Connor,et al.  Interaction between 16S ribosomal RNA and ribosomal protein S12: differential effects of paromomycin and streptomycin. , 1991, Biochimie.

[91]  H. Noller,et al.  Model for the three-dimensional folding of 16 S ribosomal RNA. , 1988, Journal of molecular biology.

[92]  R. Schroeder Dissecting RNA function , 1994, Nature.

[93]  H. Noller,et al.  A base pair between tRNA and 23S rRNA in the peptidyl transferase centre of the ribosome , 1995, Nature.

[94]  Marina Lotti,et al.  Characterisation of a mutant from Escherichia coli lacking protein L15 and localisation of protein L15 by immuno-electron microscopy , 2004, Molecular and General Genetics MGG.

[95]  S. Liebman,et al.  An accuracy center in the ribosome conserved over 2 billion years. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[96]  S. Douthwaite Functional interactions within 23S rRNA involving the peptidyltransferase center , 1992, Journal of bacteriology.

[97]  R. Kominami,et al.  A Base Substitution within the GTPase-associated Domain of Mammalian 28 S Ribosomal RNA Causes High Thiostrepton Accessibility (*) , 1995, The Journal of Biological Chemistry.

[98]  L. Brakier-Gingras,et al.  A mutation in the 530 loop of Escherichia coli 16S ribosomal RNA causes resistance to streptomycin. , 1988, Nucleic acids research.

[99]  K. Nierhaus,et al.  Minimal set of ribosomal components for reconstitution of the peptidyltransferase activity. , 1982, The EMBO journal.

[100]  N. Tanaka,et al.  Interaction of kanamycin and related antibiotics with the large subunit of ribosomes and the inhibition of translocation. , 1978, Biochemical and biophysical research communications.

[101]  S. Douthwaite,et al.  Erythromycin binding is reduced in ribosomes with conformational alterations in the 23 S rRNA peptidyl transferase loop. , 1993, Journal of molecular biology.

[102]  G. Kramer,et al.  Structure, Function, and Genetics of Ribosomes , 1986, Springer Series in Molecular Biology.

[103]  J. Frank,et al.  A model of protein synthesis based on cryo-electron microscopy of the E. coli ribosome , 1995, Nature.

[104]  R. Brimacombe,et al.  The structure of ribosomal RNA: a three-dimensional jigsaw puzzle. , 1995, European journal of biochemistry.

[105]  S. Douthwaite,et al.  Ribosomal proteins L11 and L10.(L12)4 and the antibiotic thiostrepton interact with overlapping regions of the 23 S rRNA backbone in the ribosomal GTPase centre. , 1993, Journal of molecular biology.

[106]  J. Nyborg,et al.  The crystal structure of elongation factor EF-Tu from Thermus aquaticus in the GTP conformation. , 1993, Structure.

[107]  D. Draper,et al.  Recognition of the highly conserved GTPase center of 23 S ribosomal RNA by ribosomal protein L11 and the antibiotic thiostrepton. , 1991, Journal of molecular biology.

[108]  K. Nierhaus,et al.  Ribosomal Decoding Processes at Codons in the A or P Sites Depend Differently on 2′-OH Groups (*) , 1995, The Journal of Biological Chemistry.

[109]  H. Noller Peptidyl transferase: protein, ribonucleoprotein, or RNA? , 1993, Journal of bacteriology.

[110]  M. Rodnina,et al.  Codon‐dependent conformational change of elongation factor Tu preceding GTP hydrolysis on the ribosome. , 1995, The EMBO journal.

[111]  H. Wittmann Protein Biosynthesis and Its Inhibition by Antibiotics , 1988 .

[112]  H. Noller,et al.  A functional pseudoknot in 16S ribosomal RNA. , 1991, The EMBO journal.

[113]  R. Hilgenfeld,et al.  Crystal structure of active elongation factor Tu reveals major domain rearrangements , 1993, Nature.

[114]  U. Geigenmüller,et al.  Significance of the third tRNA binding site, the E site, on E. coli ribosomes for the accuracy of translation: an occupied E site prevents the binding of non‐cognate aminoacyl‐tRNA to the A site. , 1990, The EMBO journal.

[115]  R. Garrett,et al.  Fine structure of the peptidyl transferase centre on 23 S-like rRNAs deduced from chemical probing of antibiotic-ribosome complexes. , 1995, Journal of molecular biology.

[116]  O. Uhlenbeck,et al.  Inhibition of the hammerhead ribozyme by neomycin. , 1969, RNA.

[117]  K. Nierhaus,et al.  Kinetic and thermodynamic parameters for tRNA binding to the ribosome and for the translocation reaction. , 1992, The Journal of biological chemistry.

[118]  K. Nierhaus An elongation factor turn-on , 1996, Nature.

[119]  M. Ehrenberg,et al.  Ribosomal RNA and protein mutants resistant to spectinomycin. , 1990, The EMBO journal.

[120]  E. Cundliffe Involvement of Specific Portions of Ribosomal RNA in Defined Ribosomal Functions: A Study Utilizing Antibiotics , 1986 .

[121]  Harry F. Noller,et al.  Transfer RNA shields specific nucleotides in 16S ribosomal RNA from attack by chemical probes , 1986, Cell.

[122]  H. Urlaub,et al.  Peptide Environment of the Peptidyl Transferase Center from Escherichia coli 70 S Ribosomes as Determined by Thermoaffinity Labeling with Dihydrospiramycin (*) , 1995, The Journal of Biological Chemistry.

[123]  B. Golden,et al.  Structural Studies on Prokaryotic Ribosomal Proteins , 1993 .

[124]  H. Moine,et al.  Mutations in helix 34 of Escherichia coli 16 S ribosomal RNA have multiple effects on ribosome function and synthesis. , 1994, Journal of molecular biology.

[125]  S. Douthwaite,et al.  The antibiotics micrococcin and thiostrepton interact directly with 23S rRNA nucleotides 1067A and 1095A. , 1994, Nucleic acids research.

[126]  D. Draper,et al.  Detection of a key tertiary interaction in the highly conserved GTPase center of large subunit ribosomal RNA. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[127]  K. Nierhaus,et al.  Proteins fro Escherichia coli ribosomes involved in the binding of erythromycin. , 1978, Journal of molecular biology.

[128]  R. Gutell,et al.  Collection of small subunit (16S- and 16S-like) ribosomal RNA structures: 1994. , 1993, Nucleic acids research.

[129]  G. Dinos,et al.  Interaction between the antibiotic spiramycin and a ribosomal complex active in peptide bond formation. , 1993, Biochemistry.

[130]  H. Noller,et al.  Hydroxyl radical footprinting of ribosomal proteins on 16S rRNA. , 1995, RNA.

[131]  H. Rheinberger,et al.  Three tRNA binding sites on Escherichia coli ribosomes. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[132]  K. Nierhaus,et al.  Protein involved in the binding of dihydrostreptomycin to ribosomes of Escherichia coli. , 1973, Journal of molecular biology.

[133]  M. Nomura,et al.  Colicin E3 induced cleavage of 16S ribosomal ribonucleic acid; blocking effects of certain antibiotics. , 1973, Biochemistry.

[134]  D. Svergun,et al.  Solution scattering from 50S ribosomal subunit resolves inconsistency between electron microscopic models. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[135]  M. Di Giambattista,et al.  Affinity labeling of the virginiamycin S binding site on bacterial ribosome. , 1990, Biochemistry.

[136]  David E. Draper,et al.  Thermodynamics of RNA unfolding: stabilization of a ribosomal RNA tertiary structure by thiostrepton and ammonium ion. , 1995, Journal of molecular biology.

[137]  Michael R. Green,et al.  Small molecules that selectively block RNA binding of HIV-1 rev protein inhibit rev function and viral production , 1993, Cell.

[138]  U. Geigenmüller,et al.  Tetracycline can inhibit tRNA binding to the ribosomal P site as well as to the A site. , 1986, European journal of biochemistry.

[139]  R. Brimacombe,et al.  A model for the spatial arrangement of the proteins in the large subunit of the Escherichia coli ribosome. , 1988, The EMBO journal.

[140]  M van Heel,et al.  The 70S Escherichia coli ribosome at 23 A resolution: fitting the ribosomal RNA. , 1995, Structure.

[141]  P. H. Anborgh,et al.  New antibiotic that acts specifically on the GTP‐bound form of elongation factor Tu. , 1991, The EMBO journal.

[142]  C. Sigmund,et al.  Antibiotic resistance mutations in 16S and 23S ribosomal RNA genes of Escherichia coli. , 1984, Nucleic acids research.

[143]  C. Spahn,et al.  The elongating ribosome: structural and functional aspects. , 1995, Biochemistry and cell biology = Biochimie et biologie cellulaire.