Insights into erythromycin action from studies of its activity as inducer of resistance

Weisblum, Bernard

doi:10.1128/aac.39.4.797

Cited by 261 publications

(215 citation statements)

References 59 publications

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“…Expression of cmlA is inducible by sub-inhibitory levels of chloramphenicol and the region upstream of cmlA includes a leader peptide and inverted repeats capable of forming alternate stem-loop structures . These features are similar to those found upstream of the inducible cat and ermC genes of Gram-positive bacteria which are known to Mobile gene cassettes be regulated by translational attenuation (for reviews see Lovett, 1990;Weisblum, 1995).…”

Section: Expression Of the Cmla Genesupporting

confidence: 53%

Gene cassettes: a new class of mobile element

1995

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Section: Expression Of the Cmla Genesupporting

confidence: 53%

Gene cassettes: a new class of mobile element

1995

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“…Some biochemical evidence argues that the action of macrolide antibiotics depends on the properties of the polypeptide being synthesized by the drug-bound ribosome as revealed by differential inhibition of in vitro translation of certain model and natural mRNA templates (8)(9)(10). Consistent with these observations, the sites of macrolide-induced programmed ribosome stalling at the regulatory leader ORFs, which control expression of the macrolide resistance genes, are defined by the sequence of the encoded nascent peptide (11)(12)(13)(14)(15). Importantly, the protein-specific action of macrolides is readily observed in vivo, because treatment of sensitive cells with even very high concentrations of antibiotics allows the continued production of a subset of cellular polypeptides (8).…”

supporting

confidence: 53%

The general mode of translation inhibition by macrolide antibiotics

Kannan

Kanabar

Schryer

et al. 2014

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

162

179

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Significance Macrolide antibiotics inhibit translation by binding in the ribosomal nascent peptide exit tunnel. It was believed that macrolides interfere with protein synthesis by obstructing the egress of nascent proteins. In contrast to this view, the results of ribosome profiling analysis suggest that the main mode of macrolide action is context-specific inhibition of peptide bond formation. The ribosome with a macrolide molecule bound in the tunnel is impaired in catalysis of peptide bond formation between specific combinations of the peptidyl donors and aminoacyl acceptors, leading to interruption of translation when such problematic substrates are encountered. These findings underscore the existence of a link between the ribosomal tunnel and the peptidyl transferase center and pave the way for development of superior antibiotics.

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“…Sequence effects have also been reported for erythromycin, which poorly inhibits polyphenylalanine synthesis (29 -31) but strongly inhibits incorporation of basic amino acids into nascent peptides (32). Most interestingly, expression of erythromycin resistance genes is regulated with the help of the peptide sequence-specific inhibitory properties of erythromycin (33,34).…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Macrolide Action

Lovmar

Tenson

Ehrenberg

2004

Journal of Biological Chemistry

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Members of the macrolide class of antibiotics inhibit peptide elongation on the ribosome by binding close to the peptidyltransferase center and blocking the peptide exit tunnel in the large ribosomal subunit. We have studied the modes of action of the macrolides josamycin, with a 16-membered lactone ring, and erythromycin, with a 14-membered lactone ring, in a cell-free mRNA translation system with pure components from Escherichia coli. We have found that the average lifetime on the ribosome is 3 h for josamycin and less than 2 min for erythromycin and that the dissociation constants for josamycin and erythromycin binding to the ribosome are 5.5 and 11 nM, respectively. Josamycin slows down formation of the first peptide bond of a nascent peptide in an amino acid-dependent way and completely inhibits formation of the second or third peptide bond, depending on peptide sequence. Erythromycin allows formation of longer peptide chains before the onset of inhibition. Both drugs stimulate the rate constants for drop-off of peptidyl-tRNA from the ribosome. In the josamycin case, drop-off is much faster than drug dissociation, whereas these rate constants are comparable in the erythromycin case. Therefore, at a saturating drug concentration, synthesis of fulllength proteins is completely shut down by josamycin but not by erythromycin. It is likely that the bacteriotoxic effects of the drugs are caused by a combination of inhibition of protein elongation, on the one hand, and depletion of the intracellular pools of aminoacyltRNAs available for protein synthesis by drop-off and incomplete peptidyl-tRNA hydrolase activity, on the other hand.

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Insights into erythromycin action from studies of its activity as inducer of resistance

Cited by 261 publications

References 59 publications

Gene cassettes: a new class of mobile element

Gene cassettes: a new class of mobile element

The general mode of translation inhibition by macrolide antibiotics

Kinetics of Macrolide Action

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