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| Status |
Public on Jun 24, 2024 |
| Title |
RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution |
| Organism |
Escherichia coli BW25113 |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Bacteria often evolve antibiotic resistance through mutagenesis. However, the processes causing the mutagenesis have not been fully resolved. Here we found that a broad range of ribosome-targeting antibiotics caused mutations through an underexplored pathway. Focusing on the clinically important aminoglycoside gentamicin, we found that the translation inhibitor caused genome-wide premature stalling of RNA polymerase (RNAP) in a loci-dependent manner. Further analysis showed that the stalling was caused by disruption of transcription-translation coupling. Anti-intuitively, the stalled RNAPs subsequently induced lesions to the DNA via transcription-coupled repair. While most of the bacteria were killed by genotoxicity, a small subpopulation acquired mutations via SOS-induced mutagenesis. Given that these processes were triggered shortly after antibiotic addition, resistance rapidly emerged in the population. Our work revealed a new mechanism of action of ribosomal antibiotics, illustrates the importance of dissecting the complex interplay between multiple molecular processes in understanding antibiotic efficacy, and suggests new strategies for countering the development of resistance.
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| Overall design |
To investigate the secondary effect of gentamicin treatment, which is transcription elongation chaos and mutagensis, we performed RNA-seq and 3' -end-seq to profile transcription dynamics and genome re-sequencing to identify mutations.
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| Contributor(s) |
Zheng Y, Chai R, Wang T, Xu Z, He Y, Shen P |
| Citation(s) |
39097616 |
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| Submission date |
Aug 09, 2023 |
| Last update date |
Sep 23, 2024 |
| Contact name |
Jintao Liu |
| E-mail(s) |
jintaoliu@tsinghua.edu.cn
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| Organization name |
Tsinghua University
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| Street address |
Haidian District
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| City |
Beijing |
| ZIP/Postal code |
100084 |
| Country |
China |
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| Platforms (1) |
| GPL27123 |
Illumina NovaSeq 6000 (Escherichia coli BW25113) |
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| Samples (24)
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| GSM7698567 |
Gentamicin, 13 min, RNA-seq, wildtype |
| GSM7698568 |
Gentamicin, 20 min, RNA-seq, wildtype |
| GSM7698569 |
Gentamicin, 40 min, RNA-seq, wildtype |
| GSM7698570 |
Gentamicin, 60 min, RNA-seq, wildtype |
| GSM7698571 |
Gentamicin, 74 min, RNA-seq, wildype |
| GSM7698572 |
Gentamicin, 110 min, RNA-seq, wildtype |
| GSM7698573 |
0 min, RNA-seq, Δmfd |
| GSM7698574 |
Gentamicin, 60 min, RNA-seq, Δmfd |
| GSM7698575 |
Gentamicin, 110 min, RNA-seq, Δmfd |
| GSM7698576 |
0 min, replicate 1, 3'-end-seq, wildtype |
| GSM7698577 |
0 min, replicate 2, 3'-end-seq, wildtype |
| GSM7698578 |
Gentamicin, 6 min, 3'-end-seq, wildtype |
| GSM7698579 |
Gentamicin, 13 min, 3'-end-seq, wildtype |
| GSM7698580 |
Gentamicin, 20 min, 3'-end-seq, wildtype |
| GSM7698581 |
Gentamicin, 40 min, 3'-end-seq, wildtype |
| GSM7698582 |
Gentamicin, 60 min, 3'-end-seq, wildtype |
| GSM7698583 |
Gentamicin, 74 min, 3'-end-seq, wildype |
| GSM7698584 |
Gentamicin, 110 min, 3'-end-seq, wildtype |
| GSM7698585 |
0 min, 3'-end-seq, Δmfd |
| GSM7698586 |
Gentamicin, 60 min, 3'-end-seq, Δmfd |
| GSM7698587 |
Gentamicin, 110 min, 3'-end-seq, Δmfd |
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| Relations |
| BioProject |
PRJNA1003865 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE240474_PRSE_end_CPM.xlsx |
146.1 Mb |
(ftp)(http) |
XLSX |
| GSE240474_qualified_gene_TPM.csv.gz |
324.2 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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