The bacterial ribosome, a promising focus for structure-based drug design

Knowles, David J. C.; Foloppe, Nicolas; Matassova, Natalia; Murchie, Alastair I. H.

doi:10.1016/s1471-4892(02)00205-9

Cited by 58 publications

(35 citation statements)

References 55 publications

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“…[16][17][18]106,107) As to macrolides, the 3D structures of the ligands adjacent to peptidyl-transferase center on the 50S ribosomal subunit reveal how an inhibitor binds to the target, thus facilitating computational analysis of other factors that contribute to binding, such as shape and electrostatic complementlity. 18,[106][107][108] This structure-based drug-design approach produces promising potential macrolide derivatives against respiratory tract pathogens resistant to macrolides and ketolides, penicillin, chloramphenicol, and sulphamethoxazole.…”

Section: New Approaches To Development Of Novel Antibioticsmentioning

confidence: 99%

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

Yoneyama

Katsumata

2006

Bioscience, Biotechnology, and Biochemistry

241

196

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Section: New Approaches To Development Of Novel Antibioticsmentioning

confidence: 99%

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

Yoneyama

Katsumata

2006

Bioscience, Biotechnology, and Biochemistry

241

196

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“…As expected, inhibition of ribosomal activity and, hence, of de novo synthesis of proteins will automatically slow down cell growth. This makes the ribosome a highly suitable target for development of drugs that aim at reducing the growth rate of bacterial cells as well as of human tumor cells (Knowles et al 2002;Tenson and Mankin 2006). Approximately 50% of the antibiotics currently used in clinical medicine for treatment of bacterial infections target the ribosome.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide modifications and tRNA anticodon–mRNA codon interactions on the ribosome

Allnér

Nilsson²

2011

RNA

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We have carried out molecular dynamics simulations of the tRNA anticodon and mRNA codon, inside the ribosome, to study the effect of the common tRNA modifications cmo 5 U34 and m 6 A37. In tRNA Val , these modifications allow all four nucleotides to be successfully read at the wobble position in a codon. Previous data suggest that entropic effects are mainly responsible for the extended reading capabilities, but detailed mechanisms have remained unknown. We have performed a wide range of simulations to elucidate the details of these mechanisms at the atomic level and quantify their effects: extensive free energy perturbation coupled with umbrella sampling, entropy calculations of tRNA (free and bound to the ribosome), and thorough structural analysis of the ribosomal decoding center. No prestructuring effect on the tRNA anticodon stem-loop from the two modifications could be observed, but we identified two mechanisms that may contribute to the expanded decoding capability by the modifications: The further reach of the cmo 5 U34 allows an alternative outer conformation to be formed for the noncognate base pairs, and the modification results in increased contacts between tRNA, mRNA, and the ribosome.

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“…Bacterial protein synthesis inhibitors include the macrolides (e.g., erythromycin, clarithromycin, and azithromycin), clindamycin, chloramphenicol, the aminoglycosides (e.g., streptomycin, gentamicin, and amikacin), and the tetracyclines (2,18,49). The newest class of antibacterials, the synthetic oxazolidinones (exemplified by linezolid, the only novel and approved ribosomal inhibitor), also inhibit protein synthesis (21,45). Protein synthesis is the cellular process most frequently targeted by naturally occurring antibacterials, providing compelling evolutionary evidence for the susceptibility of this process to antibiotic intervention (21).…”

mentioning

confidence: 99%

Discovery and Analysis of 4 H -Pyridopyrimidines, a Class of Selective Bacterial Protein Synthesis Inhibitors

Ribble

Hill

Ochsner

et al. 2010

Antimicrob Agents Chemother

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Bacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. We have developed a poly(U) mRNA-directed aminoacylation/translation protein synthesis system composed of phenyltRNA synthetases, ribosomes, and ribosomal factors from Escherichia coli. This system, utilizing purified components, has been used for high-throughput screening of a small-molecule chemical library. We have identified a series of compounds that inhibit protein synthesis with 50% inhibitory concentrations (IC 50 s) ranging from 3 to 14 M. This series of compounds all contained the same central scaffold composed of tetrahydropyrido[4,3-d]pyrimidin-4-ol (e.g., 4H-pyridopyrimidine). All analogs contained an ortho pyridine ring attached to the central scaffold in the 2 position and either a five-or a six-member ring tethered to the 6-methylene nitrogen atom of the central scaffold. These compounds inhibited the growth of E. coli, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, with MICs ranging from 0.25 to 32 g/ml. Macromolecular synthesis (MMS) assays with E. coli and S. aureus confirmed that antibacterial activity resulted from specific inhibition of protein synthesis. Assays were developed for the steps performed by each component of the system in order to ascertain the target of the compounds, and the ribosome was found to be the site of inhibition.

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The bacterial ribosome, a promising focus for structure-based drug design

Cited by 58 publications

References 55 publications

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

Antibiotic Resistance in Bacteria and Its Future for Novel Antibiotic Development

Nucleotide modifications and tRNA anticodon–mRNA codon interactions on the ribosome

Discovery and Analysis of 4 H -Pyridopyrimidines, a Class of Selective Bacterial Protein Synthesis Inhibitors

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