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dc.contributor.author
Scaiola, Alain
dc.contributor.author
Leibundgut, Marc
dc.contributor.author
Boehringer, Daniel
dc.contributor.author
Caspers, Patrick
dc.contributor.author
Bur, Daniel
dc.contributor.author
Locher, Hans H.
dc.contributor.author
Rueedi, Georg
dc.contributor.author
Ritz, Daniel
dc.date.accessioned
2019-04-16T08:38:18Z
dc.date.available
2019-04-16T03:21:33Z
dc.date.available
2019-04-16T08:38:18Z
dc.date.issued
2019
dc.identifier.issn
2045-2322
dc.identifier.other
10.1038/s41598-019-42155-4
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/338181
dc.identifier.doi
10.3929/ethz-b-000338181
dc.description.abstract
Oxazolidinones are synthetic antibiotics used for treatment of infections caused by Gram-positive bacteria. They target the bacterial protein synthesis machinery by binding to the peptidyl transferase centre (PTC) of the ribosome and interfering with the peptidyl transferase reaction. Cadazolid is the first member of quinoxolidinone antibiotics, which are characterized by combining the pharmacophores of oxazolidinones and fluoroquinolones, and it is evaluated for treatment of Clostridium difficile gastrointestinal infections that frequently occur in hospitalized patients. In vitro protein synthesis inhibition by cadazolid was shown in Escherichia coli and Staphylococcus aureus, including an isolate resistant against linezolid, the prototypical oxazolidinone antibiotic. To better understand the mechanism of inhibition, we determined a 3.0 Å cryo-electron microscopy structure of cadazolid bound to the E. coli ribosome in complex with mRNA and initiator tRNA. Here we show that cadazolid binds with its oxazolidinone moiety in a binding pocket in close vicinity of the PTC as observed previously for linezolid, and that it extends its unique fluoroquinolone moiety towards the A-site of the PTC. In this position, the drug inhibits protein synthesis by interfering with the binding of tRNA to the A-site, suggesting that its chemical features also can enable the inhibition of linezolid-resistant strains.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Nature
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Structural basis of translation inhibition by cadazolid, a novel quinoxolidinone antibiotic
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2019-04-04
ethz.journal.title
Scientific Reports
ethz.journal.volume
9
en_US
ethz.journal.abbreviated
Sci Rep
ethz.pages.start
5634
en_US
ethz.size
9 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02521 - Inst. f. Molekularbiologie u. Biophysik / Inst. Molecular Biology and Biophysics::03556 - Ban, Nenad / Ban, Nenad
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02521 - Inst. f. Molekularbiologie u. Biophysik / Inst. Molecular Biology and Biophysics::03556 - Ban, Nenad / Ban, Nenad
ethz.date.deposited
2019-04-16T03:21:34Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2019-04-16T08:38:31Z
ethz.rosetta.lastUpdated
2024-02-02T07:40:25Z
ethz.rosetta.versionExported
true
ethz.COinS
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