Insights into the Stress Response Triggered by Kasugamycin in Escherichia coli

Müller, Christian; Sokol, Lena; Vesper, Oliver; Sauert, Martina; Moll, Isabella

doi:10.3390/antibiotics5020019

Cited by 13 publications

(19 citation statements)

References 47 publications

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“…Msm-RpoB-N434T was less rifampicin tolerant than its parent strain, but kasugamycin was less potent at decreasing rifampicin tolerance further ( Figure 2E ). Since other reported activities of kasugamycin ( Lange et al, 2017 ; Müller et al, 2016 ; Kaberdina et al, 2009 ) would not be affected by a single point mutation in the rpoB gene, we conclude that the major mechanism by which kasugamycin increased rifampicin susceptibility is by decreasing mistranslation-induced protein variants.…”

Section: Resultsmentioning

confidence: 65%

“…GatCAB-mediated mistranslation is not due to ribosomal decoding errors – but rather due to misacylated Glu-tRNA Gln and Asp-tRNA Asn complexes taking part in translation ( Su et al, 2016 ). In addition to other reported activities in E. coli ( Lange et al, 2017 ; Müller et al, 2016 ; Kaberdina et al, 2009 ; Moll and Bläsi, 2002 ), the aminoglycoside kasugamycin decreased ribosomal misreading of mRNA ( van Buul et al, 1984 ), but it was not known if it could also decrease errors due to translation of misacylated tRNAs, as the indirect tRNA aminoacylation pathway is not present in E. coli .…”

Section: Resultsmentioning

confidence: 97%

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Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

Chaudhuri

Zimmerman

et al. 2018

eLife

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Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of Mycobacterium tuberculosis with increased rates of error in gene translation (mistranslation) involving the indirect tRNA-aminoacylation pathway have increased tolerance to the first-line antibiotic rifampicin. Here, we identify that the aminoglycoside kasugamycin can specifically decrease mistranslation due to the indirect tRNA pathway. Kasugamycin but not the aminoglycoside streptomycin, can limit emergence of rifampicin resistance in vitro and increases mycobacterial susceptibility to rifampicin both in vitro and in a murine model of infection. Moreover, despite parenteral administration of kasugamycin being unable to achieve the in vitro minimum inhibitory concentration, kasugamycin alone was able to significantly restrict growth of Mycobacterium tuberculosis in mice. These data suggest that pharmacologically reducing mistranslation may be a novel mechanism for targeting bacterial adaptation.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 97%

Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

Chaudhuri

Zimmerman

et al. 2018

eLife

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“…We used derivatives of E. coli strain K-12 MG1655 ( Blattner et al, 1997 ; Müller et al, 2016 ) when addressing effects of antibiotic treatments and amino acid starvation, and derivatives of E. coli strain BW27784 containing a native copy of the mazEF operon ( Khlebnikov et al, 2001 ) for experiments with arabinose-inducible systems. The open reading frame of the employed reporter gene Em gfp ΔACA is devoid of ACA sites ( Sauert, 2015 ; Oron-Gottesman et al, 2016 ), whilst the amino acid sequence corresponds to the wild-type fast-folding Emerald GFP ( Tsien, 1998 ).…”

Section: Methodsmentioning

confidence: 99%

MazF activation promotes translational heterogeneity of thegrcAmRNA inEscherichia colipopulations

Nikolić

Didara

Moll

2017

PeerJ

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Bacteria adapt to adverse environmental conditions by altering gene expression patterns. Recently, a novel stress adaptation mechanism has been described that allows Escherichia coli to alter gene expression at the post-transcriptional level. The key player in this regulatory pathway is the endoribonuclease MazF, the toxin component of the toxin-antitoxin module mazEF that is triggered by various stressful conditions. In general, MazF degrades the majority of transcripts by cleaving at ACA sites, which results in the retardation of bacterial growth. Furthermore, MazF can process a small subset of mRNAs and render them leaderless by removing their ribosome binding site. MazF concomitantly modifies ribosomes, making them selective for the translation of leaderless mRNAs. In this study, we employed fluorescent reporter-systems to investigate mazEF expression during stressful conditions, and to infer consequences of the mRNA processing mediated by MazF on gene expression at the single-cell level. Our results suggest that mazEF transcription is maintained at low levels in single cells encountering adverse conditions, such as antibiotic stress or amino acid starvation. Moreover, using the grcA mRNA as a model for MazF-mediated mRNA processing, we found that MazF activation promotes heterogeneity in the grcA reporter expression, resulting in a subpopulation of cells with increased levels of GrcA reporter protein.

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“…Therefore, we examined the effect of the antibiotic Kas, which is also known to confer stress [ 30 ]. Kas is an aminoglycoside antibiotic that inhibits protein synthesis during the step of translation initiation [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Evidence for a cytoplasmic pool of ribosome-free mRNAs encoding inner membrane proteins in Escherichia coli

et al. 2017

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Translation-independent mRNA localization represents an emerging concept in cell biology. In Escherichia coli, mRNAs encoding integral membrane proteins (MPRs) are targeted to the membrane where they are translated by membrane associated ribosomes and the produced proteins are inserted into the membrane co-translationally. In order to better understand aspects of the biogenesis and localization of MPRs, we investigated their subcellular distribution using cell fractionation, RNA-seq and qPCR. The results show that MPRs are overrepresented in the membrane fraction, as expected, and depletion of the signal recognition particle-receptor, FtsY reduced the amounts of all mRNAs on the membrane. Surprisingly, however, MPRs were also found relatively abundant in the soluble ribosome-free fraction and their amount in this fraction is increased upon overexpression of CspE, which was recently shown to interact with MPRs. CspE also conferred a positive effect on the membrane-expression of integral membrane proteins. We discuss the possibility that the effects of CspE overexpression may link the intriguing subcellular localization of MPRs to the cytosolic ribosome-free fraction with their translation into membrane proteins and that the ribosome-free pool of MPRs may represent a stage during their targeting to the membrane, which precedes translation.

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Insights into the Stress Response Triggered by Kasugamycin in Escherichia coli

Cited by 13 publications

References 47 publications

Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

MazF activation promotes translational heterogeneity of thegrcAmRNA inEscherichia colipopulations

Evidence for a cytoplasmic pool of ribosome-free mRNAs encoding inner membrane proteins in Escherichia coli

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