Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria

Daniel Dar; Maya Shamir; J. R. Mellin; Mikael Koutero; Noam Stern-Ginossar; Pascale Cossart; Rotem Sorek

doi:10.1126/science.aad9822

Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria

Daniel Dar, Maya Shamir, J. R. Mellin, Mikael Koutero, Noam Stern-Ginossar, Pascale Cossart, Rotem Sorek

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

Abstract

Riboswitches and attenuators are cis-regulatory RNA elements, most of which control bacterial gene expression via metabolite-mediated, premature transcription termination. We developed an unbiased experimental approach for genome-wide discovery of such ribo-regulators in bacteria. We also devised an experimental platform that quantitatively measures the in vivo activity of all such regulators in parallel and enables rapid screening for ribo-regulators that respond to metabolites of choice. Using this approach, we detected numerous antibioticresponsive ribo-regulators that control antibiotic resistance genes in pathogens and in the human microbiome. Studying one such regulator in Listeria monocytogenes revealed an attenuation mechanism mediated by antibiotic-stalled ribosomes. Our results expose broad roles for conditional termination in regulating antibiotic resistance and provide a tool for discovering riboswitches and attenuators that respond to previously unknown ligands.

Original language	English
Article number	aad9822
Journal	Science
Volume	352
Issue number	6282
DOIs	https://doi.org/10.1126/science.aad9822
State	Published - 8 Apr 2016

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title = "Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria",

abstract = "Riboswitches and attenuators are cis-regulatory RNA elements, most of which control bacterial gene expression via metabolite-mediated, premature transcription termination. We developed an unbiased experimental approach for genome-wide discovery of such ribo-regulators in bacteria. We also devised an experimental platform that quantitatively measures the in vivo activity of all such regulators in parallel and enables rapid screening for ribo-regulators that respond to metabolites of choice. Using this approach, we detected numerous antibioticresponsive ribo-regulators that control antibiotic resistance genes in pathogens and in the human microbiome. Studying one such regulator in Listeria monocytogenes revealed an attenuation mechanism mediated by antibiotic-stalled ribosomes. Our results expose broad roles for conditional termination in regulating antibiotic resistance and provide a tool for discovering riboswitches and attenuators that respond to previously unknown ligands.",

author = "Daniel Dar and Maya Shamir and Mellin, {J. R.} and Mikael Koutero and Noam Stern-Ginossar and Pascale Cossart and Rotem Sorek",

note = "We thank O. Wurtzel, I. Karunker, S. Doron, G. Amitai, G. Ofir, A. Millman, Y. Voichek, S. Melamed, and R. Nir-Paz for insightful discussion. R.S. was supported, in part, by the Israel Science Foundation (personal grant 1303/12 and I-CORE grant 1796/12), the European Research Council (ERC)–Starting Grants program (grant 260432), Human Frontier Science Program (grant RGP0011/2013 to R.S. and P.C), the Abisch-Frenkel foundation, the Pasteur-Weizmann council grant (to R.S and P.C), the Minerva Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, and by a Deutsch-Israelische Projektkooperation grant from the Deutsche Forschungsgemeinschaft. P.C was supported by an ERC–Advanced Grants grant (BacCellEpi, #670823). Reference IRB for the microbiome analysis is 0315-15-HMO. Sequencing data was deposited in the European Nucleotide Database (ENA), accession no. PRJEB12568. D.D. and R.S. are inventors on U.S. provisional patent application 62/200,662.",

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AU - Dar, Daniel

AU - Shamir, Maya

AU - Mellin, J. R.

AU - Koutero, Mikael

AU - Stern-Ginossar, Noam

AU - Cossart, Pascale

AU - Sorek, Rotem

N1 - We thank O. Wurtzel, I. Karunker, S. Doron, G. Amitai, G. Ofir, A. Millman, Y. Voichek, S. Melamed, and R. Nir-Paz for insightful discussion. R.S. was supported, in part, by the Israel Science Foundation (personal grant 1303/12 and I-CORE grant 1796/12), the European Research Council (ERC)–Starting Grants program (grant 260432), Human Frontier Science Program (grant RGP0011/2013 to R.S. and P.C), the Abisch-Frenkel foundation, the Pasteur-Weizmann council grant (to R.S and P.C), the Minerva Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, and by a Deutsch-Israelische Projektkooperation grant from the Deutsche Forschungsgemeinschaft. P.C was supported by an ERC–Advanced Grants grant (BacCellEpi, #670823). Reference IRB for the microbiome analysis is 0315-15-HMO. Sequencing data was deposited in the European Nucleotide Database (ENA), accession no. PRJEB12568. D.D. and R.S. are inventors on U.S. provisional patent application 62/200,662.

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N2 - Riboswitches and attenuators are cis-regulatory RNA elements, most of which control bacterial gene expression via metabolite-mediated, premature transcription termination. We developed an unbiased experimental approach for genome-wide discovery of such ribo-regulators in bacteria. We also devised an experimental platform that quantitatively measures the in vivo activity of all such regulators in parallel and enables rapid screening for ribo-regulators that respond to metabolites of choice. Using this approach, we detected numerous antibioticresponsive ribo-regulators that control antibiotic resistance genes in pathogens and in the human microbiome. Studying one such regulator in Listeria monocytogenes revealed an attenuation mechanism mediated by antibiotic-stalled ribosomes. Our results expose broad roles for conditional termination in regulating antibiotic resistance and provide a tool for discovering riboswitches and attenuators that respond to previously unknown ligands.

AB - Riboswitches and attenuators are cis-regulatory RNA elements, most of which control bacterial gene expression via metabolite-mediated, premature transcription termination. We developed an unbiased experimental approach for genome-wide discovery of such ribo-regulators in bacteria. We also devised an experimental platform that quantitatively measures the in vivo activity of all such regulators in parallel and enables rapid screening for ribo-regulators that respond to metabolites of choice. Using this approach, we detected numerous antibioticresponsive ribo-regulators that control antibiotic resistance genes in pathogens and in the human microbiome. Studying one such regulator in Listeria monocytogenes revealed an attenuation mechanism mediated by antibiotic-stalled ribosomes. Our results expose broad roles for conditional termination in regulating antibiotic resistance and provide a tool for discovering riboswitches and attenuators that respond to previously unknown ligands.

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VL - 352

JO - Science

JF - Science

IS - 6282

M1 - aad9822

ER -

Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria

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