The bacterial ribosome as a target for antibiotics

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.

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

[2]  H. Zeichhardt,et al.  Architecture of the Escherichia coli ribosome as determined by immune electron microscopy. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J A Lake,et al.  Ribosome structure determined by electron microscopy of Escherichia coli small subunits, large subunits and monomeric ribosomes. , 1976, Journal of molecular biology.

[4]  D. Vazquez Inhibitors of Protein Biosynthesis , 1979, Molecular Biology Biochemistry and Biophysics.

[5]  A. Yonath,et al.  Parameters for crystal growth of ribosomal subunits , 1982, Journal of cellular biochemistry.

[6]  F. Schmidt,et al.  Site of action of a ribosomal RNA methylase responsible for resistance to erythromycin and other antibiotics. , 1983, The Journal of biological chemistry.

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

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

[9]  D. Moras,et al.  Preliminary X-ray investigation of 70 S ribosome crystals from Thermus thermophilus. , 1989, Journal of molecular biology.

[10]  E. Cundliffe,et al.  Methylation of 23S rRNA caused by tlrA (ermSF), a tylosin resistance determinant from Streptomyces fradiae , 1989, Journal of bacteriology.

[11]  Walter E. Hill,et al.  The Ribosome : structure, function, and evolution , 1990 .

[12]  E. Cundliffe,et al.  Cloning of tlrD, a fourth resistance gene, from the tylosin producer, Streptomyces fradiae. , 1991, Gene.

[13]  A. Spirin,et al.  Thermus thermophilus ribosomes for crystallographic studies. , 1991, Biochimie.

[14]  H. Bartels,et al.  Characterization and preliminary attempts for derivatization of crystals of large ribosomal subunits from Haloarcula marismortui diffracting to 3 A resolution. , 1991, Journal of molecular biology.

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

[16]  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.

[17]  J. Hoogmartens,et al.  Macrolides, chemistry, pharmacology and clinical uses , 1993 .

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

[19]  B. Weisblum,et al.  Insights into erythromycin action from studies of its activity as inducer of resistance , 1995, Antimicrobial agents and chemotherapy.

[20]  B. Weisblum Erythromycin resistance by ribosome modification , 1995, Antimicrobial agents and chemotherapy.

[21]  J. Puglisi,et al.  Structure of the A Site of Escherichia coli 16S Ribosomal RNA Complexed with an Aminoglycoside Antibiotic , 1996, Science.

[22]  T. Cech,et al.  Peptide bond formation by in vitro selected ribozymes , 1997, Nature.

[23]  K. Nguyen,et al.  Properties of NAD-dependent glutamate dehydrogenase from the tylosin producer Streptomyces fradiae , 1997 .

[24]  T. Pallasch Macrolide antibiotics. , 1997, Dentistry today.

[25]  Anders Liljas,et al.  Structural aspects of protein synthesis , 2004, Nature Structural Biology.

[26]  H. Noller,et al.  Ribosome-catalyzed peptide-bond formation with an A-site substrate covalently linked to 23S ribosomal RNA. , 1998, Science.

[27]  J. Puglisi,et al.  Structural origins of gentamicin antibiotic action , 1998, The EMBO journal.

[28]  A. Mankin,et al.  A ketolide resistance mutation in domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase centre , 1999, Molecular microbiology.

[29]  A. Mankin,et al.  Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center. , 1999, Journal of molecular biology.

[30]  S. T. Gregory,et al.  Erythromycin resistance mutations in ribosomal proteins L22 and L4 perturb the higher order structure of 23 S ribosomal RNA. , 1999, Journal of molecular biology.

[31]  M. Rodnina,et al.  Thiostrepton inhibits the turnover but not the GTPase of elongation factor G on the ribosome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. H. Hansen,et al.  The macrolide–ketolide antibiotic binding site is formed by structures in domains II and V of 23S ribosomal RNA , 1999, Molecular microbiology.

[33]  J. Puglisi,et al.  Recognition of the codon-anticodon helix by ribosomal RNA. , 1999, Science.

[34]  J. Frank,et al.  Structural studies of the translational apparatus. , 1999, Current opinion in structural biology.

[35]  F. Schluenzen,et al.  Structure of Functionally Activated Small Ribosomal Subunit , 2000 .

[36]  A. Bryskier Ketolides-telithromycin, an example of a new class of antibacterial agents. , 2000, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[37]  O. Uhlenbeck,et al.  Intact aminoacyl-tRNA is required to trigger GTP hydrolysis by elongation factor Tu on the ribosome. , 2000, Biochemistry.

[38]  V. Ramakrishnan,et al.  Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics , 2000, Nature.

[39]  T. Steitz,et al.  The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. , 2000, Science.

[40]  M. Heel,et al.  Visualization of the Translational Elongation Cycle by Cryo-Electron Microscopy , 2000 .

[41]  B. Vester,et al.  Inhibition of the ribosomal peptidyl transferase reaction by the mycarose moiety of the antibiotics carbomycin, spiramycin and tylosin. , 2000, Journal of molecular biology.

[42]  F. Schluenzen,et al.  Structure of Functionally Activated Small Ribosomal Subunit at 3.3 Å Resolution , 2000, Cell.

[43]  T. Steitz,et al.  The structural basis of ribosome activity in peptide bond synthesis. , 2000, Science.

[44]  Roger A. Garrett,et al.  The Ribosome, Structure, Function, Antibiotics, and Cellular Interactions , 2000 .

[45]  C. Vonrhein,et al.  Structure of the 30S ribosomal subunit , 2000, Nature.

[46]  R. Brennan,et al.  The conformations of the macrolide antibiotics erythromycin A, azithromycin and clarithromycin in aqueous solution: a 1H NMR study , 2000 .

[47]  M. Jacobs,et al.  Mutations in 23S rRNA and Ribosomal Protein L4 Account for Resistance in Pneumococcal Strains Selected In Vitro by Macrolide Passage , 2000, Antimicrobial Agents and Chemotherapy.

[48]  K. Shaw,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 , 2000, Antimicrobial Agents and Chemotherapy.

[49]  V. Ramakrishnan,et al.  The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit , 2000, Cell.

[50]  A Yonath,et al.  Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3 , 2001, The EMBO journal.

[51]  E Westhof,et al.  Crystal structure of paromomycin docked into the eubacterial ribosomal decoding A site. , 2001, Structure.

[52]  A. Mankin,et al.  Binding Site of Macrolide Antibiotics on the Ribosome: New Resistance Mutation Identifies a Specific Interaction of Ketolides with rRNA , 2001, Journal of bacteriology.

[53]  A. Mankin,et al.  A novel site of antibiotic action in the ribosome: Interaction of evernimicin with the large ribosomal subunit , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[54]  V. Ramakrishnan,et al.  Recognition of Cognate Transfer RNA by the 30S Ribosomal Subunit , 2001, Science.

[55]  A. Mankin,et al.  Short peptides conferring resistance to macrolide antibiotics , 2001, Peptides.

[56]  Frank Schluenzen,et al.  High Resolution Structure of the Large Ribosomal Subunit from a Mesophilic Eubacterium , 2001, Cell.

[57]  F. Schluenzen,et al.  Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria , 2001, Nature.

[58]  J Frank,et al.  The polypeptide tunnel system in the ribosome and its gating in erythromycin resistance mutants of L4 and L22. , 2001, Molecular cell.

[59]  Harry F. Noller,et al.  The Path of Messenger RNA through the Ribosome , 2001, Cell.

[60]  S. Douthwaite,et al.  Macrolide Resistance Conferred by Base Substitutions in 23S rRNA , 2001, Antimicrobial Agents and Chemotherapy.

[61]  T. Earnest,et al.  Crystal Structure of the Ribosome at 5.5 Å Resolution , 2001, Science.

[62]  E. Westhof,et al.  Crystal structure of a complex between the aminoglycoside tobramycin and an oligonucleotide containing the ribosomal decoding a site. , 2002, Chemistry & biology.

[63]  S. Lovas,et al.  Structure and stability of oxaphosphetes formed as intermediates in the reaction of tertiary phosphine oxides and acetylenic derivatives , 2002 .

[64]  J. Poehlsgaard,et al.  The macrolide binding site on the bacterial ribosome. , 2002, Current drug targets. Infectious disorders.

[65]  C. Yanofsky,et al.  Instruction of Translating Ribosome by Nascent Peptide , 2002, Science.

[66]  S. Douthwaite,et al.  Activity of the Ketolide Telithromycin Is Refractory to Erm Monomethylation of Bacterial rRNA , 2002, Antimicrobial Agents and Chemotherapy.

[67]  S. Douthwaite,et al.  Resistance to the macrolide antibiotic tylosin is conferred by single methylations at 23S rRNA nucleotides G748 and A2058 acting in synergy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[68]  B. Vester,et al.  Interaction of Avilamycin with Ribosomes and Resistance Caused by Mutations in 23S rRNA , 2002, Antimicrobial Agents and Chemotherapy.

[69]  Poul Nissen,et al.  The structures of four macrolide antibiotics bound to the large ribosomal subunit. , 2002, Molecular cell.

[70]  Jill K Thompson,et al.  The protein synthesis inhibitors, oxazolidinones and chloramphenicol, cause extensive translational inaccuracy in vivo. , 2002, Journal of Molecular Biology.

[71]  M. Ehrenberg,et al.  Regulatory Nascent Peptides in the Ribosomal Tunnel , 2002, Cell.

[72]  A. Liljas,et al.  L22 ribosomal protein and effect of its mutation on ribosome resistance to erythromycin. , 2002, Journal of molecular biology.

[73]  R. Leclercq,et al.  Mechanisms of resistance to macrolides, lincosamides, and ketolides , 2002 .

[74]  Thomas A Steitz,et al.  Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit. , 2003, Journal of molecular biology.

[75]  Scott M Stagg,et al.  Incorporation of aminoacyl-tRNA into the ribosome as seen by cryo-electron microscopy , 2003, Nature Structural Biology.

[76]  Frank Schluenzen,et al.  Structural insight into the role of the ribosomal tunnel in cellular regulation , 2003, Nature Structural Biology.

[77]  Eric Westhof,et al.  Crystal structure of geneticin bound to a bacterial 16S ribosomal RNA A site oligonucleotide. , 2003, Journal of molecular biology.

[78]  W. S. Champney Bacterial ribosomal subunit assembly is an antibiotic target. , 2003, Current topics in medicinal chemistry.

[79]  William K. Ridgeway,et al.  X-ray crystal structures of the WT and a hyper-accurate ribosome from Escherichia coli , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[80]  R. Berisio,et al.  Structural Insight into the Antibiotic Action of Telithromycin against Resistant Mutants , 2003, Journal of bacteriology.

[81]  Frank Schluenzen,et al.  Structural basis of the ribosomal machinery for peptide bond formation, translocation, and nascent chain progression. , 2003, Molecular cell.

[82]  Thomas A Steitz,et al.  The structural basis of large ribosomal subunit function. , 2002, Annual review of biochemistry.

[83]  J. Frank,et al.  Visualizing tmRNA Entry into a Stalled Ribosome , 2003, Science.

[84]  R. Zarivach,et al.  Structural basis for the antibiotic activity of ketolides and azalides. , 2003, Structure.

[85]  Måns Ehrenberg,et al.  The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. , 2003, Journal of molecular biology.

[86]  V. Ramakrishnan,et al.  Insights into the decoding mechanism from recent ribosome structures. , 2003, Trends in biochemical sciences.

[87]  S. Douthwaite,et al.  The avilamycin resistance determinants AviRa and AviRb methylate 23S rRNA at the guanosine 2535 base and the uridine 2479 ribose , 2003, Molecular microbiology.

[88]  N. Ban,et al.  Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins , 2004, Nature.

[89]  H. Noller The driving force for molecular evolution of translation. , 2004, RNA.

[90]  T. Steitz,et al.  The roles of ribosomal proteins in the structure assembly, and evolution of the large ribosomal subunit. , 2004, Journal of molecular biology.

[91]  J. Poehlsgaard,et al.  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 , 2004, Molecular microbiology.

[92]  H. Bartels,et al.  Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin , 2004, BMC Biology.

[93]  D. Pardo,et al.  Properties of ribosomes from erythromycin resistant mutants of Escherichia coli , 1977, Molecular and General Genetics MGG.

[94]  J. Poehlsgaard,et al.  The structural basis of macrolide-ribosome binding assessed using mutagenesis of 23S rRNA positions 2058 and 2059. , 2004, Journal of molecular biology.

[95]  C. Gualerzi,et al.  The translation initiation functions of IF2: targets for thiostrepton inhibition. , 2004, Journal of molecular biology.

[96]  Jill K Thompson,et al.  Methylation of 16S ribosomal RNA and resistance to the aminoglycoside antibiotics gentamicin and kanamycin determined by DNA from the gentamicin-producer, Micromonospora purpurea , 2004, Molecular and General Genetics MGG.

[97]  Rachel Green,et al.  The Active Site of the Ribosome Is Composed of Two Layers of Conserved Nucleotides with Distinct Roles in Peptide Bond Formation and Peptide Release , 2004, Cell.

[98]  M. Roberts Resistance to macrolide, lincosamide, streptogramin, ketolide, and oxazolidinone antibiotics , 2004, Molecular biotechnology.

[99]  Annette Sievers,et al.  The ribosome as an entropy trap. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[100]  C. Spahn,et al.  Throwing a spanner in the works: antibiotics and the translation apparatus , 1996, Journal of Molecular Medicine.

[101]  R. Green,et al.  RNA chaperone activity of large ribosomal subunit proteins from Escherichia coli. , 2004, RNA.

[102]  I. Morrissey,et al.  In Vitro Activities of Telithromycin, Linezolid, and Quinupristin-Dalfopristin against Streptococcus pneumoniae with Macrolide Resistance Due to Ribosomal Mutations , 2004, Antimicrobial Agents and Chemotherapy.

[103]  J. Poehlsgaard,et al.  Ketolide Antimicrobial Activity Persists after Disruption of Interactions with Domain II of 23S rRNA , 2004, Antimicrobial Agents and Chemotherapy.

[104]  Koreaki Ito,et al.  Control of SecA and SecM translation by protein secretion. , 2004, Current opinion in microbiology.

[105]  D. Farrell,et al.  Activities of Telithromycin against 13,874 Streptococcus pneumoniae Isolates Collected between 1999 and 2003 , 2004, Antimicrobial Agents and Chemotherapy.

[106]  A. Yonath,et al.  Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin , 2004, Molecular microbiology.

[107]  S. Osawa,et al.  Biochemical and genetic studies on two different types of erythromycin resistant mutants of Escherichia coli with altered ribosomal proteins , 1973, Molecular and General Genetics MGG.

[108]  J. Poehlsgaard,et al.  The tylosin-resistance methyltransferase RlmA(II) (TlrB) modifies the N-1 position of 23S rRNA nucleotide G748. , 2004, Journal of molecular biology.

[109]  A. Bashan,et al.  Ribosomal crystallography: initiation, peptide bond formation, and amino acid polymerization are hampered by antibiotics. , 2004, Annual review of microbiology.

[110]  A. Mankin Ribosomal Antibiotics , 2004, Molecular Biology.

[111]  H. Noller,et al.  mRNA Helicase Activity of the Ribosome , 2005, Cell.

[112]  R. Zarivach,et al.  23S rRNA base pair 2057-2611 determines ketolide susceptibility and fitness cost of the macrolide resistance mutation 2058A-->G. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[113]  Joachim Frank,et al.  The role of tRNA as a molecular spring in decoding, accommodation, and peptidyl transfer , 2005, FEBS letters.

[114]  A. Mankin,et al.  Binding Site of the Bridged Macrolides in the Escherichia coli Ribosome , 2005, Antimicrobial Agents and Chemotherapy.

[115]  E. Westhof,et al.  Mutagenesis of 16S rRNA C1409-G1491 base-pair differentiates between 6'OH and 6'NH3+ aminoglycosides. , 2005, Journal of molecular biology.

[116]  Thomas Hermann,et al.  Drugs targeting the ribosome. , 2005, Current opinion in structural biology.

[117]  E. J. Murgola,et al.  Interaction of Thiostrepton and Elongation Factor-G with the Ribosomal Protein L11-binding Domain* , 2005, Journal of Biological Chemistry.

[118]  R. Green,et al.  An Active Role for tRNA in Decoding Beyond Codon:Anticodon Pairing , 2005, Science.

[119]  G. Ashley,et al.  Translation and protein synthesis: macrolides. , 2005, Chemical reviews.

[120]  R. Micura,et al.  Chemical engineering of the peptidyl transferase center reveals an important role of the 2′-hydroxyl group of A2451 , 2005, Nucleic acids research.

[121]  A Mutation in the Decoding Center of Thermus thermophilus 16S rRNA Suggests a Novel Mechanism of Streptomycin Resistance , 2005, Journal of bacteriology.

[122]  T. Hermann,et al.  Molecular recognition by glycoside pseudo base pairs and triples in an apramycin-RNA complex. , 2005, Angewandte Chemie.

[123]  Gregor Blaha,et al.  Structures of MLSBK Antibiotics Bound to Mutated Large Ribosomal Subunits Provide a Structural Explanation for Resistance , 2005, Cell.

[124]  Henri Grosjean,et al.  Fine-tuning of RNA functions by modification and editing , 2005 .

[125]  K. Bush,et al.  In Vitro Activities of Novel 2-Fluoro-Naphthyridine-Containing Ketolides , 2005, Antimicrobial Agents and Chemotherapy.