Antibiotics and the ribosome

Tenson, Tanel; Mankin, Alexander S.

doi:10.1111/j.1365-2958.2006.05063.x

Cited by 142 publications

(120 citation statements)

References 109 publications

(173 reference statements)

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“…The bacterial ribosome is a common target for clinically relevant antibiotic drugs (18,19), and its intracellular concentration is high, i.e., Ϸ20 M in E. coli (20). Macrolides and ketolides bind with high affinity to the 23S rRNA of the 50S ribosomal subunit (21).…”

Section: Discussionmentioning

confidence: 99%

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Fange

Nilsson²,

Tenson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to ''mask'' the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens.antibiotic resistance ͉ efflux pump inhibition ͉ macrolides

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Section: Discussionmentioning

confidence: 99%

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Fange

Nilsson²,

Tenson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…2A). The altered ribosomal distribution in the presence of gentamicin could be caused by cellfixation artifacts (33), gentamicin-induced cellular stress (34,35), a reduction in the ribosome recycling rate (36), or an increase in the ratio of monosomes to polysomes (37).…”

Section: Use Of Immunoelectron Microscopy and An Antibody-independentmentioning

confidence: 99%

Spatially segregated transcription and translation in cells of the endomembrane-containing bacterium Gemmata obscuriglobus

Gottshall

Seebart

Gatlin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The dogma of coupled transcription and translation in bacteria has been challenged by recent reports of spatial segregation of these processes within the relatively simple cellular organization of the model organisms Escherichia coli and Bacillus subtilis. The bacterial species Gemmata obscuriglobus possesses an extensive endomembrane system. The membranes generate a very convoluted intracellular architecture in which some of the cell's ribosomes appear to have less direct access to the cell's nucleoid(s) than others. This observation prompted us to test the hypothesis that a substantial proportion of G. obscuriglobus translation may be spatially segregated from transcription. Using immunofluorescence and immunoelectron microscopy, we showed that translating ribosomes are localized throughout the cell, with a quantitatively greater proportion found in regions distal to nucleoid(s). Our results extend information about the phylogenetic and morphological diversity of bacteria in which the spatial organization of transcription and translation has been studied. These findings also suggest that endomembranes may provide an obstacle to colocated transcription and translation, a role for endomembranes that has not been reported previously for a prokaryotic organism. Our studies of G. obscuriglobus may provide a useful background for consideration of the evolutionary development of eukaryotic cellular complexity and how it led to decoupled processes of gene expression in eukaryotes.

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“…In a striking contrast, the distribution of sites of antibiotic action in the large ribosomal subunit is highly constrained. Despite the enormous size of the large subunit, the multiplicity of activities in which it is involved, and the diversity of drugs that inhibit the large subunit functions, all clinically relevant antibiotics act on essentially one site: the peptidyltransferase center (PTC) 3 and the adjacent region of the nascent peptide exit tunnel (5,7,8,17,18). Only two other sites in the bacterial large ribosomal sub-unit, the GTPase-associated center and the translation factor binding region, are targeted by a few other known antibiotics (19 -23).…”

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confidence: 99%

Potential New Antibiotic Sites in the Ribosome Revealed by Deleterious Mutations in RNA of the Large Ribosomal Subunit

Yassin¹,

Mankin

2007

Journal of Biological Chemistry

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The ribosome is the main target for antibiotics that inhibit protein biosynthesis. Despite the chemical diversity of the known antibiotics that affect functions of the large ribosomal subunit, these drugs act on only a few sites corresponding to some of the known functional centers. We have used a genetic approach for identifying structurally and functionally critical sites in the ribosome that can be used as new antibiotic targets. By using randomly mutagenized rRNA genes, we mapped rRNA sites where nucleotide alterations impair the ribosome function or assembly and lead to a deleterious phenotype. A total of 77 single-point deleterious mutations were mapped in 23 S rRNA and ranked according to the severity of their deleterious phenotypes. Many of the mutations mapped to familiar functional sites that are targeted by known antibiotics. However, a number of mutations were located in previously unexplored regions. The distribution of the mutations in the spatial structure of the ribosome showed a strong bias, with the strongly deleterious mutations being mainly localized at the interface of the large subunit and the mild ones on the solvent side. Five sites where deleterious mutations tend to cluster within discrete rRNA elements were identified as potential new antibiotic targets. One of the sites, the conserved segment of helix 38, was studied in more detail. Although the ability of the mutant 50 S subunits to associate with 30 S subunits was impaired, the lethal effect of mutations in this rRNA element was unrelated to its function as an intersubunit bridge. Instead, mutations in this region had a profound deleterious effect on the ribosome assembly.

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Antibiotics and the ribosome

Cited by 142 publications

References 109 publications

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Drug efflux pump deficiency and drug target resistance masking in growing bacteria

Spatially segregated transcription and translation in cells of the endomembrane-containing bacterium Gemmata obscuriglobus

Potential New Antibiotic Sites in the Ribosome Revealed by Deleterious Mutations in RNA of the Large Ribosomal Subunit

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