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HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase

Author

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  • Ilana Kaspy

    (Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem)

  • Eitan Rotem

    (Racah Institute of Physics and the Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University)

  • Noga Weiss

    (Racah Institute of Physics and the Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University)

  • Irine Ronin

    (Racah Institute of Physics and the Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University)

  • Nathalie Q. Balaban

    (Racah Institute of Physics and the Center for Nanoscience and Nanotechnology, Edmond J. Safra Campus, The Hebrew University)

  • Gad Glaser

    (Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem)

Abstract

Bacterial persistence has been shown to be an underlying factor in the failure of antibiotic treatments. Although many pathways, among them the stringent response and toxin–antitoxin modules, have been linked to antibiotic persistence, a clear molecular mechanism for the growth arrest that characterizes persistent bacteria remained elusive. Here, we screened an expression library for putative targets of HipA, the first toxin linked to persistence, and a serine/threonine kinase. We found that the expression of GltX, the glutamyl-tRNA-synthetase, reverses the toxicity of HipA and prevents persister formation. We show that upon HipA expression, GltX undergoes phosphorylation at Ser239, its ATP-binding site. This phosphorylation leads to accumulation of uncharged tRNAGlu in the cell, which results in the activation of the stringent response. Our findings demonstrate a mechanism for persister formation by the hipBA toxin–antitoxin module and provide an explanation for the long-observed connection between persistence and the stringent response.

Suggested Citation

  • Ilana Kaspy & Eitan Rotem & Noga Weiss & Irine Ronin & Nathalie Q. Balaban & Gad Glaser, 2013. "HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase," Nature Communications, Nature, vol. 4(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms4001
    DOI: 10.1038/ncomms4001
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    Cited by:

    1. Xiangkai Zhen & Yongyu Wu & Jinli Ge & Jiaqi Fu & Le Ye & Niannian Lin & Zhijie Huang & Zihe Liu & Zhao-qing Luo & Jiazhang Qiu & Songying Ouyang, 2022. "Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Ying Xiang & Kunpeng Zhu & Kaiyuan Min & Yaowen Zhang & Jiangfeng Liu & Kangkang Liu & Yiran Han & Xinge Li & Xinying Du & Xin Wang & Ying Huang & Xinping Li & Yuqian Peng & Chaojie Yang & Hongbo Liu , 2024. "Characterization of a Salmonella enterica serovar Typhimurium lineage with rough colony morphology and multidrug resistance," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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