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Translation error clusters induced by aminoglycoside antibiotics.

ABSTRACT: Aminoglycoside antibiotics target the ribosome and induce mistranslation, yet which translation errors induce bacterial cell death is unclear. The analysis of cellular proteins by quantitative mass spectrometry shows that bactericidal aminoglycosides induce not only single translation errors, but also clusters of errors in full-length proteins in vivo with as many as four amino acid substitutions in a row. The downstream errors in a cluster are up to 10,000-fold more frequent than the first error and independent of the intracellular aminoglycoside concentration. The prevalence, length, and composition of error clusters depends not only on the misreading propensity of a given aminoglycoside, but also on its ability to inhibit ribosome translocation along the mRNA. Error clusters constitute a distinct class of misreading events in vivo that may provide the predominant source of proteotoxic stress at low aminoglycoside concentration, which is particularly important for the autocatalytic uptake of the drugs.

SUBMITTER: Wohlgemuth I

PROVIDER: S-EPMC7987974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Translation Error Clusters Induced by Aminoglycoside Antibiotics

Project description:Aminoglycoside antibiotics target the ribosome and induce mistranslation, yet which translation errors induce bacterial cell death is unclear. The analysis of cellular proteins by quantitative mass spectrometry shows that bactericidal aminoglycosides induce not only single errors, but also clusters of errors in full-length proteins in vivo with as much as four amino acid substitutions in a row. The downstream errorsin a cluster are up to 10,000-fold more frequent than the first error and independent of the intracellular aminoglycoside concentration. The prevalence, length, and composition of error clusters dependsnot only on the misreading propensity of a given aminoglycoside, but also on its ability to inhibit ribosome translocation along the mRNA. Error clusters constitute a new class of misreading events in vivo that may provide the predominant source of proteotoxic stress at low aminoglycoside concentration, which is particularly important for the autocatalytic uptake of the drugs.

2021-04-06 | PXD022098 | Pride

Translation Error Clusters Induced by Aminoglycoside Antibiotics

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Translation Error Clusters Induced by Aminoglycoside Antibiotics

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TRPV4 enhances the cellular uptake of aminoglycoside antibiotics.

Project description:The cochlea and kidney are susceptible to aminoglycoside-induced toxicity. The non-selective cation channel TRPV4 is expressed in kidney distal tubule cells, and hair cells and the stria vascularis in the inner ear. To determine whether TRPV4 is involved in aminoglycoside trafficking, we generated a murine proximal-tubule cell line (KPT2) and a distal-tubule cell line (KDT3). TRPV4 expression was confirmed in KDT3 cells but not in KPT2 cells. Removal of extracellular Ca(2+) significantly enhanced gentamicin-Texas-Red (GTTR) uptake by KDT3, indicative of permeation through non-selective cation channels. To determine whether TRPV4 is permeable to GTTR, stable cell lines were generated that express TRPV4 in KPT2 (KPT2-TRPV4). KPT2-TRPV4 cells took up more GTTR than control cell lines (KPT2-pBabe) in the absence of extracellular Ca(2+). TRPV4-dependent GTTR uptake was abolished by a point mutation within the crucial pore region of the channel, suggesting that GTTR permeates the TRPV4 channel. In an endolymph-like extracellular environment, clearance of GTTR was attenuated from KPT2-TRPV4 cells in a TRPV4-dependent fashion. We propose that TRPV4 has a role in aminoglycoside uptake and retention in the cochlea.

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Transcriptional response to aminoglycoside antibiotics in cochlear hair cells at 3 hour

Project description:We purified Atoh1-GFP positive hair cells from organotypic cultures of P1 cochlea 3 hours after 0.5mM gentamicin treatment and performed RNA sequencing to profile the early transcriptional response of hair cells to aminoglycoside antibiotics. Levels of mRNA in gentamicin-treated hair cells (three replicates) were compared to untreated hair cells (three replicates). GFP negative, non-hair cells populations from treated organs were compared to those from untreated organs (three replicates for each condition).

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