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

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Title: Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
Authors: Wong, J
David, S
Sanchez Garrido, J
Woo, J
Low, WW
Morecchiato, F
Giani, T
Rossolini, GM
Beis, K
Brett, S
Clements, A
Aaenensen, D
Rouskin, S
Frankel, G
Item Type: Journal Article
Abstract: Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae (KP), modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. Analysis of large KP 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 KP 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 towards treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c>t transition mediates an intramolecular 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.
Issue Date: 12-Sep-2022
Date of Acceptance: 9-Aug-2022
URI: http://hdl.handle.net/10044/1/98978
DOI: 10.1073/pnas.2203593119
ISSN: 0027-8424
Publisher: National Academy of Sciences
Start Page: 1
End Page: 12
Journal / Book Title: Proceedings of the National Academy of Sciences of USA
Volume: 119
Issue: 38
Copyright Statement: © 2022 the Author(s). Published by PNAS.This open access article is distributed underCreativeCommons Attribution License 4.0 (CC BY).
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 107057/Z/15/Z
MR/R502376/1
Keywords: Antibiotic resistance
Carbapenems
Klebsiella pneumoniae
Outer membrane porins
Synonymous mutations
Animals
Anti-Bacterial Agents
Bacterial Proteins
Carbapenems
Klebsiella pneumoniae
Mice
Microbial Sensitivity Tests
Phylogeny
Porins
RNA, Messenger
beta-Lactamases
Animals
Mice
Klebsiella pneumoniae
Carbapenems
beta-Lactamases
Bacterial Proteins
Porins
RNA, Messenger
Anti-Bacterial Agents
Microbial Sensitivity Tests
Phylogeny
Publication Status: Published
Online Publication Date: 2022-09-12
Appears in Collections:Department of Surgery and Cancer
Cell and Molecular Biology
Faculty of Medicine
Faculty of Natural Sciences



This item is licensed under a Creative Commons License Creative Commons