BibTex format
@article{Wong:2022:10.1073/pnas.2203593119,
author = {Wong, J and David, S and Sanchez, Garrido J and Woo, J and Low, WW and Morecchiato, F and Giani, T and Rossolini, GM and Beis, K and Brett, S and Clements, A and Aaenensen, D and Rouskin, S and Frankel, G},
doi = {10.1073/pnas.2203593119},
journal = {Proceedings of the National Academy of Sciences of USA},
pages = {1--12},
title = {Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure},
url = {http://dx.doi.org/10.1073/pnas.2203593119},
volume = {119},
year = {2022}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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.
AU - Wong,J
AU - David,S
AU - Sanchez,Garrido J
AU - Woo,J
AU - Low,WW
AU - Morecchiato,F
AU - Giani,T
AU - Rossolini,GM
AU - Beis,K
AU - Brett,S
AU - Clements,A
AU - Aaenensen,D
AU - Rouskin,S
AU - Frankel,G
DO - 10.1073/pnas.2203593119
EP - 12
PY - 2022///
SN - 0027-8424
SP - 1
TI - Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure
T2 - Proceedings of the National Academy of Sciences of USA
UR - http://dx.doi.org/10.1073/pnas.2203593119
UR - http://pnas.org/doi/full/10.1073/pnas.2203593119
UR - http://hdl.handle.net/10044/1/98978
VL - 119
ER -
