Context-specific action of macrolide antibiotics on the eukaryotic ribosome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA689836 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13362514.fastq.gz | Fastqsanger.gz | |||
| SRR13362515.fastq.gz | Fastqsanger.gz | |||
| SRR13362516.fastq.gz | Fastqsanger.gz | |||
| SRR13362517.fastq.gz | Fastqsanger.gz | |||
| SRR13362518.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:80S ribosomes of S.cerevisiae carry G2400A mutation in the 25S rRNA which makes them sensitive to macrolide antibiotics
2021-05-25 | GSE164275 | GEO
Project description:Macrolides are clinically important antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that macrolide antibiotics can differentially affect synthesis of individual proteins. In order to understand the general mechanism of macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of macrolide antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5' proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The sequence motifs enriched in the sites of arrest are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segments that contact the antibiotic molecule in the exit tunnel. This led to the conclusion that the general mode of macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not during in vitro protein synthesis may modulate site-specific action of macrolide antibiotics. Comparing ribosome distribution in bacterial cells treated with macrolide antibiotics against the control cells.
2014-11-03 | E-GEOD-61619 | biostudies-arrayexpress
Project description:Macrolides are clinically important antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that macrolide antibiotics can differentially affect synthesis of individual proteins. In order to understand the general mechanism of macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of macrolide antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5' proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The sequence motifs enriched in the sites of arrest are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segments that contact the antibiotic molecule in the exit tunnel. This led to the conclusion that the general mode of macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not during in vitro protein synthesis may modulate site-specific action of macrolide antibiotics.
2014-11-03 | GSE61619 | GEO
Project description:Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Cryo-EM structural analysis showed that the macrolide telithromycin binds in the tunnel of the engineered eukaryotic ribosome. Genome-wide analysis of cellular translation and biochemical studies demonstrated that the drug inhibits eukaryotic translation by preferentially stalling ribosomes at distinct sequence motifs. Context-specific action markedly depends on the macrolide structure. Eliminating macrolide-arrest motifs from a protein renders its translation macrolide-tolerant. Our data illuminate the prospects of adapting macrolides for protein-selective translation inhibition in eukaryotic cells.
| S-EPMC8121947 | biostudies-literature
Project description:We report the context-specific activity of two peptidyl transferase targeting antibiotics, chloramphenicol and linezolid. By generating ribosome profiling data in the presence or absence of either chloramphenicol or linezolid we mapped the relative change of ribosome density induced by these antibiotics. We find that both inhibitors preferentially arrest ribosomes that carry either an alanine, serine, or threonine in the penultimate (-1) position of the nascent peptide chain. Additionally ribosomes that carry a glycine in either the P site (0) or A-site (+1) counteract the inhibitory activity of both inhibitors. The context-specific action of chloramphenicol illuminates the operation of the mechanism of inducible resistance that relies on programmed drug-induced translation arrest. In addition, our findings expose the functional interplay between the nascent chain and the peptidyl transferase center.
2016-09-08 | GSE86536 | GEO
Project description:Campylobacter jejuni is a major zoonotic pathogen transmitted to humans via the food chain. C. jejuni is prevalent in chickens, a natural reservoir for this pathogenic organism. Due to the importance of macrolide antibiotics in clinical therapy of human campylobacteriosis, development of macrolide resistance in Campylobacter has become a concern for public health.To facilitate understanding the molecular basis associated with the fitness difference between Erys and Eryr Campylobacter, we compared the transcriptomes between ATCC 700819 and its isogenic Eryr transformant T.L.101 using DNA microarray.
2011-11-02 | GSE33330 | GEO
Project description:The antibiotics chloramphenicol (CHL) and oxazolidinones including linezolid (LZD) are known to inhibit mitochondrial translation. This can result in serious, potentially deadly, side effects when used therapeutically. Although the mechanism by which CHL and LZD inhibit bacterial ribosomes has been elucidated in detail, their mechanism of action against mitochondrial ribosomes has yet to be explored. CHL and oxazolidinones bind to the ribosomal peptidyl transfer center (PTC) of the bacterial ribosome and prevent incorporation of incoming amino acids under specific sequence contexts, causing ribosomes to stall only at certain sequences. Through mitoribosome profiling, we show that inhibition of mitochondrial ribosomes is similarly context-specific – CHL and LZD lead to mitoribosome stalling primarily when there is an alanine, serine, or threonine in the penultimate position of the nascent peptide chain. Our findings could help inform the rational development of future, less mitotoxic, antibiotics, which are critically needed in the current era of increasing antimicrobial resistance.
2024-10-01 | GSE273206 | GEO
Project description:Campylobacter jejuni is a major zoonotic pathogen transmitted to humans via the food chain. C. jejuni is prevalent in chickens, a natural reservoir for this pathogenic organism. Due to the importance of macrolide antibiotics in clinical therapy of human campylobacteriosis, development of macrolide resistance in Campylobacter has become a concern for public health.To facilitate understanding the molecular basis associated with the fitness difference between Erys and Eryr Campylobacter, we compared the transcriptomes between ATCC 700819 and its isogenic Eryr transformant T.L.101 using DNA microarray. The design utilized an available two color microarray slide for the entire transcriptome of Campylobacter jejuni. Four hybridizations were performed each with independently extracted samples of either macrolide susceptible ATCC 700819 cDNA samples or its isogenic Eryr transformant T.L.101 cDNA samples. A dye swap was utilized to help minimize dye dependent bias. Thus, there were four biological replicates of each sample.
2011-11-02 | E-GEOD-33330 | biostudies-arrayexpress
Project description:RNA-seq based transcriptome profiling allows a detailed molecular analysis of the E.coli transcriptome (~4200 genes) after perturbation with different antibiotics. Transcriptome fingerprints enable the identification of gene and pathway level responses to treatment to derive a mechanistic understanding of antibiotics mode of action and to differentiate antibiotics. For this goal, treatment has to be performed in a short time period and with sublethal concentrations of the antibiotics. Sublethal concentrations were chosen based on the EC90 concentration of the antibiotic necessary to change the cellular morphology compared to control conditions. Conclusions: Our study represents the first detailed analysis of E.coli transcriptomes after treatment with different antibiotics, with biologic replicates, generated by RNA-seq technology. The experimental design and data analysis reported here should provide a framework for comparative investigations of expression profiles of known and novel antibiotics. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic functions.
2019-03-25 | GSE110137 | GEO
Project description:Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.
| S-EPMC4103360 | biostudies-literature