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RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution

Author

Listed:
  • Yayun Zheng

    (Tsinghua University)

  • Ruochen Chai

    (Tsinghua University)

  • Tianmin Wang

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences
    ShanghaiTech University)

  • Zeqi Xu

    (Tsinghua University)

  • Yihui He

    (Tsinghua University)

  • Ping Shen

    (Tsinghua University)

  • Jintao Liu

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences
    Shanxi Medical University)

Abstract

Bacteria often evolve antibiotic resistance through mutagenesis. However, the processes causing the mutagenesis have not been fully resolved. Here, we find that a broad range of ribosome-targeting antibiotics cause mutations through an underexplored pathway. Focusing on the clinically important aminoglycoside gentamicin, we find that the translation inhibitor causes genome-wide premature stalling of RNA polymerase (RNAP) in a loci-dependent manner. Further analysis shows that the stalling is caused by the disruption of transcription-translation coupling. Anti-intuitively, the stalled RNAPs subsequently induce lesions to the DNA via transcription-coupled repair. While most of the bacteria are killed by genotoxicity, a small subpopulation acquires mutations via SOS-induced mutagenesis. Given that these processes are triggered shortly after antibiotic addition, resistance rapidly emerges in the population. Our work reveals a 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.

Suggested Citation

  • Yayun Zheng & Ruochen Chai & Tianmin Wang & Zeqi Xu & Yihui He & Ping Shen & Jintao Liu, 2024. "RNA polymerase stalling-derived genome instability underlies ribosomal antibiotic efficacy and resistance evolution," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50917-6
    DOI: 10.1038/s41467-024-50917-6
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    References listed on IDEAS

    as
    1. Hallie Wimberly & Chandan Shee & P. C. Thornton & Priya Sivaramakrishnan & Susan M. Rosenberg & P. J. Hastings, 2013. "R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    2. Vitaly Epshtein & Venu Kamarthapu & Katelyn McGary & Vladimir Svetlov & Beatrix Ueberheide & Sergey Proshkin & Alexander Mironov & Evgeny Nudler, 2014. "UvrD facilitates DNA repair by pulling RNA polymerase backwards," Nature, Nature, vol. 505(7483), pages 372-377, January.
    3. Grace E. Johnson & Jean-Benoît Lalanne & Michelle L. Peters & Gene-Wei Li, 2020. "Functionally uncoupled transcription–translation in Bacillus subtilis," Nature, Nature, vol. 585(7823), pages 124-128, September.
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