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

Autor: Wong JLC; Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.; Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London SW7 2AZ, United Kingdom., David S; Centre for Genomic Pathogen Surveillance, Big Data Institute, University of Oxford, Oxford OX3 7LF, United Kingdom., Sanchez-Garrido J; Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom., Woo JZ; Department of Microbiology, Harvard Medical School, Boston, MA 02115., Low WW; Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom., Morecchiato F; Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy., Giani T; Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.; Clinical Microbiology and Virology Unit, Careggi University Hospital, Florence 50134, Italy., Rossolini GM; Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.; Clinical Microbiology and Virology Unit, Careggi University Hospital, Florence 50134, Italy., Beis K; Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.; Rutherford Appleton Laboratory, Research Complex at Harwell, Didcot, Oxfordshire OX11 0FA, United Kingdom., Brett SJ; Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London SW7 2AZ, United Kingdom., Clements A; Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom., Aanensen DM; Centre for Genomic Pathogen Surveillance, Big Data Institute, University of Oxford, Oxford OX3 7LF, United Kingdom., Rouskin S; Department of Microbiology, Harvard Medical School, Boston, MA 02115., Frankel G; Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Sep 20; Vol. 119 (38), pp. e2203593119. Date of Electronic Publication: 2022 Sep 12.
DOI: 10.1073/pnas.2203593119
Abstrakt: 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.
Databáze: MEDLINE
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