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Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure

Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. An analysis of large K. pneumoniae genome collections, encompassing major healthcare-associated clones, re...

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Autores principales: Wong, Joshua L. C., David, Sophia, Sanchez-Garrido, Julia, Woo, Jia Z., Low, Wen Wen, Morecchiato, Fabio, Giani, Tommaso, Rossolini, Gian Maria, Beis, Konstantinos, Brett, Stephen J., Clements, Abigail, Aanensen, David M., Rouskin, Silvi, Frankel, Gad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499542/
https://www.ncbi.nlm.nih.gov/pubmed/36095213
http://dx.doi.org/10.1073/pnas.2203593119
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author Wong, Joshua L. C.
David, Sophia
Sanchez-Garrido, Julia
Woo, Jia Z.
Low, Wen Wen
Morecchiato, Fabio
Giani, Tommaso
Rossolini, Gian Maria
Beis, Konstantinos
Brett, Stephen J.
Clements, Abigail
Aanensen, David M.
Rouskin, Silvi
Frankel, Gad
author_facet Wong, Joshua L. C.
David, Sophia
Sanchez-Garrido, Julia
Woo, Jia Z.
Low, Wen Wen
Morecchiato, Fabio
Giani, Tommaso
Rossolini, Gian Maria
Beis, Konstantinos
Brett, Stephen J.
Clements, Abigail
Aanensen, David M.
Rouskin, Silvi
Frankel, Gad
author_sort Wong, Joshua L. C.
collection PubMed
description Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. An analysis of large K. pneumoniae genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine-to-thymine transition at position 25 (25c > t) in ompK36. We show that the 25c > t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates K. pneumoniae in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c > t transition tips the balance toward treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c > t transition mediates an intramolecular messenger RNA (mRNA) interaction between a uracil encoded by 25t and the first adenine within the Shine–Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure.
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spelling pubmed-94995422022-09-23 Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure Wong, Joshua L. C. David, Sophia Sanchez-Garrido, Julia Woo, Jia Z. Low, Wen Wen Morecchiato, Fabio Giani, Tommaso Rossolini, Gian Maria Beis, Konstantinos Brett, Stephen J. Clements, Abigail Aanensen, David M. Rouskin, Silvi Frankel, Gad Proc Natl Acad Sci U S A Biological Sciences Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. An analysis of large K. pneumoniae genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine-to-thymine transition at position 25 (25c > t) in ompK36. We show that the 25c > t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates K. pneumoniae in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c > t transition tips the balance toward treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c > t transition mediates an intramolecular messenger RNA (mRNA) interaction between a uracil encoded by 25t and the first adenine within the Shine–Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure. National Academy of Sciences 2022-09-12 2022-09-20 /pmc/articles/PMC9499542/ /pubmed/36095213 http://dx.doi.org/10.1073/pnas.2203593119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Wong, Joshua L. C.
David, Sophia
Sanchez-Garrido, Julia
Woo, Jia Z.
Low, Wen Wen
Morecchiato, Fabio
Giani, Tommaso
Rossolini, Gian Maria
Beis, Konstantinos
Brett, Stephen J.
Clements, Abigail
Aanensen, David M.
Rouskin, Silvi
Frankel, Gad
Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
title Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
title_full Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
title_fullStr Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
title_full_unstemmed Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
title_short Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
title_sort recurrent emergence of klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompk36 mrna secondary structure
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499542/
https://www.ncbi.nlm.nih.gov/pubmed/36095213
http://dx.doi.org/10.1073/pnas.2203593119
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