Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome

ABSTRACT An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus. This high-resolution structural information demonstrated that a single amino acid deletion...

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Autores principales:	Matthew J. Belousoff, Zohar Eyal, Mazdak Radjainia, Tofayel Ahmed, Rebecca S. Bamert, Donna Matzov, Anat Bashan, Ella Zimmerman, Satabdi Mishra, David Cameron, Hans Elmlund, Anton Y. Peleg, Shashi Bhushan, Trevor Lithgow, Ada Yonath
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	staphylococcus antibiotic resistance ribosomal mutations Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1ec9f31a43344b03be4992f9b65c601b
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spelling	oai:doaj.org-article:1ec9f31a43344b03be4992f9b65c601b2021-11-15T15:51:30ZStructural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome10.1128/mBio.00395-172150-7511https://doaj.org/article/1ec9f31a43344b03be4992f9b65c601b2017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00395-17https://doaj.org/toc/2150-7511ABSTRACT An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus. This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site. IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821–832, 2015, https://doi.org/10.1038/nrd4675 ). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance.Matthew J. BelousoffZohar EyalMazdak RadjainiaTofayel AhmedRebecca S. BamertDonna MatzovAnat BashanElla ZimmermanSatabdi MishraDavid CameronHans ElmlundAnton Y. PelegShashi BhushanTrevor LithgowAda YonathAmerican Society for Microbiologyarticlestaphylococcusantibiotic resistanceribosomal mutationsMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	staphylococcus antibiotic resistance ribosomal mutations Microbiology QR1-502
spellingShingle	staphylococcus antibiotic resistance ribosomal mutations Microbiology QR1-502 Matthew J. Belousoff Zohar Eyal Mazdak Radjainia Tofayel Ahmed Rebecca S. Bamert Donna Matzov Anat Bashan Ella Zimmerman Satabdi Mishra David Cameron Hans Elmlund Anton Y. Peleg Shashi Bhushan Trevor Lithgow Ada Yonath Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
description	ABSTRACT An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus. This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site. IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821–832, 2015, https://doi.org/10.1038/nrd4675 ). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance.
format	article
author	Matthew J. Belousoff Zohar Eyal Mazdak Radjainia Tofayel Ahmed Rebecca S. Bamert Donna Matzov Anat Bashan Ella Zimmerman Satabdi Mishra David Cameron Hans Elmlund Anton Y. Peleg Shashi Bhushan Trevor Lithgow Ada Yonath
author_facet	Matthew J. Belousoff Zohar Eyal Mazdak Radjainia Tofayel Ahmed Rebecca S. Bamert Donna Matzov Anat Bashan Ella Zimmerman Satabdi Mishra David Cameron Hans Elmlund Anton Y. Peleg Shashi Bhushan Trevor Lithgow Ada Yonath
author_sort	Matthew J. Belousoff
title	Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
title_short	Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
title_full	Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
title_fullStr	Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
title_full_unstemmed	Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome
title_sort	structural basis for linezolid binding site rearrangement in the <italic toggle="yes">staphylococcus aureus</italic> ribosome
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/1ec9f31a43344b03be4992f9b65c601b
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Structural Basis for Linezolid Binding Site Rearrangement in the <italic toggle="yes">Staphylococcus aureus</italic> Ribosome

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