In addition to structural modifications, carbapenem resistance is also achieved by absent or reduced OmpK36 expression. 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. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. 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. However, in the context of carbapenem treatment, the 25c > t transition tips the balance toward treatment failure, thus accounting for its recurrent emergence. pneumoniae in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis.
We show that the 25c > t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane.
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. In Klebsiella pneumoniae, modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx.
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