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

Ilana Kaspy, Eitan Rotem, Noga Weiss, Irine Ronin, Nathalie Q. Balaban and Gad Glaser ()
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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

Nature Communications, 2013, vol. 4, issue 1, 1-7

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms4001

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