Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center 1 1Edited by D. E. Draper

Kloss, Patricia; Xiong, Liqun; Shinabarger, Dean L.; Mankin, Alexander S.

doi:10.1006/jmbi.1999.3247

Cited by 198 publications

(148 citation statements)

References 39 publications

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“…S4a). Generally, archaeal ribosomes are considered more ''eukaryotic-like'' with respect to their antibiotic specificities; however, this is not the case for the oxazolidinones as they have been shown to bind and/or inhibit both archaeal and bacterial (including mitochondrial) ribosomes but not to interact with human cytoplasmic ribosomes (13,14). In the H50S-linezolid structure (U.S. patent number 6,947,845 B2), the drug appears to bind deeper in the binding pocket when compared with the position in D50S, which could result from the shifted position of U2504.…”

Section: (4)mentioning

confidence: 99%

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The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

Wilson

Schluenzen

Harms

et al. 2008

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

274

256

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The oxazolidinones represent the first new class of antibiotics to enter into clinical usage within the past 30 years, but their binding site and mechanism of action has not been fully characterized. We have determined the crystal structure of the oxazolidinone linezolid bound to the Deinococcus radiodurans 50S ribosomal subunit. Linezolid binds in the A site pocket at the peptidyltransferase center of the ribosome overlapping the aminoacyl moiety of an A-site bound tRNA as well as many clinically important antibiotics. Binding of linezolid stabilizes a distinct conformation of the universally conserved 23S rRNA nucleotide U2585 that would be nonproductive for peptide bond formation. In conjunction with available biochemical data, we present a model whereby oxazolidinones impart their inhibitory effect by perturbing the correct positioning of tRNAs on the ribosome.

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Section: (4)mentioning

confidence: 99%

“…1A and supporting information (SI) Fig. S1] (14)(15)(16)(17)(18)(19). Although translation is recognized as the main target of oxazolidinones, there still remains some controversy as to the step of inhibition.…”

mentioning

confidence: 99%

The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

Wilson

Schluenzen

Harms

et al. 2008

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

274

256

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“…It appears to be more difficult to generate mutants of Enterococcus faecium resistant to linezolid than for quinupristin-dalfopristin (22). The specific point mutations causing resistance in Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, and other organisms have been mapped to several different locations in domain V of the 23S ribosomal RNA of the 50S subunit of the ribosome (23)(24)(25), and studies in resistant clinical isolates reveal similar mutations (26 -28; Moellering RC Jr., Tsiodras S, Gold H, Meka V, Sakoulas G, Eliopoulos GM, et al Unpublished data). Resistance to the oxazolidinones based on inactivation has not been demonstrated in any bacterial species tested.…”

Section: Mechanism Of Action and Resistancementioning

confidence: 99%

Linezolid: The First Oxazolidinone Antimicrobial

2003

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Linezolid is the first of a new class of antimicrobial agents, the oxazolidinones, to be approved for clinical use in the United States and elsewhere. The drug is a totally synthetic compound, which lessens the likelihood of naturally occurring resistance mechanisms. It has excellent activity against virtually all important gram-positive pathogens, including methicillin-resistant staphylococci, penicillin-resistant pneumococci, macrolide-resistant streptococci, and vancomycin-resistant enterococci. Development of resistance to the compound has been infrequent thus far. Linezolid is 100% bioavailable, so it can be given in equal doses orally or parenterally. Its elimination half-life allows dosing twice per day, and alteration of drug dosage is not required in patients with impaired renal or hepatic function. Linezolid has approved indications for skin and soft tissue infections; lower respiratory tract infections; and vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia. The drug has an acceptable profile of adverse events, but reversible myelosuppression has occurred in patients receiving high doses for more than 2 weeks.

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“…1) (18)(19)(20)(21). It remained unexplained, however, why LZD, which readily interfered with in vivo protein synthesis or cell-free translation (22), failed to inhibit peptide bond formation between fMet-tRNA and puromycin (18,23).…”

mentioning

confidence: 99%

Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center

Marks

Kannan

Roncase

et al. 2016

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

145

162

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The first broad-spectrum antibiotic chloramphenicol and one of the newest clinically important antibacterials, linezolid, inhibit protein synthesis by targeting the peptidyl transferase center of the bacterial ribosome. Because antibiotic binding should prevent the placement of aminoacyl-tRNA in the catalytic site, it is commonly assumed that these drugs are universal inhibitors of peptidyl transfer and should readily block the formation of every peptide bond. However, our in vitro experiments showed that chloramphenicol and linezolid stall ribosomes at specific mRNA locations. Treatment of bacterial cells with high concentrations of these antibiotics leads to preferential arrest of translation at defined sites, resulting in redistribution of the ribosomes on mRNA. Antibiotic-mediated inhibition of protein synthesis is most efficient when the nascent peptide in the ribosome carries an alanine residue and, to a lesser extent, serine or threonine in its penultimate position. In contrast, the inhibitory action of the drugs is counteracted by glycine when it is either at the nascent-chain C terminus or at the incoming aminoacyl-tRNA. The context-specific action of chloramphenicol illuminates the operation of the mechanism of inducible resistance that relies on programmed drug-induced translation arrest. In addition, our findings expose the functional interplay between the nascent chain and the peptidyl transferase center.ribosome | antibiotics | protein synthesis | nascent peptide | oxazolidinones

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Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center 1 1Edited by D. E. Draper

Cited by 198 publications

References 39 publications

The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning

Linezolid: The First Oxazolidinone Antimicrobial

Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center

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