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Research Article

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

Zohar Eyal, Donna Matzov, Miri Krupkin, Itai Wekselman, Susanne Paukner, Ella Zimmerman, Haim Rozenberg, Anat Bashan, and Ada Yonath
  1. aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
  2. bNabriva Therapeutics AG, 1110 Vienna, Austria

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PNAS October 27, 2015 112 (43) E5805-E5814; first published October 13, 2015; https://doi.org/10.1073/pnas.1517952112
Zohar Eyal
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Donna Matzov
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Miri Krupkin
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Itai Wekselman
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Susanne Paukner
bNabriva Therapeutics AG, 1110 Vienna, Austria
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Ella Zimmerman
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Haim Rozenberg
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Anat Bashan
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Ada Yonath
aDepartment of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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  • For correspondence: ada.yonath@weizmann.ac.il
  1. Contributed by Ada Yonath, September 17, 2015 (sent for review August 19, 2015)

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Significance

Clinical use of the currently available antibiotics is severely compromised by the increasing resistance to them, acquired by the natural bacterial capability to manipulate their genomes. Many existing antibiotics target the fundamental process of protein biosynthesis, mainly by paralyzing the ribosome. Although antibiotics’ modes of action are similar across most eubacteria, species specificity has been detected. We determined the structures of the large ribosomal subunit from Staphylococcus aureus, a pathogenic bacterial species with a known capacity to become multiresistant, and of its complexes with known antibiotic compounds, as well as with a novel potential pleuromutilin derivative. Our new insights provide unique chemical tools for enhanced distinction between pathogens and the useful benign microbiome, as well as for suggesting novel sites for potential future antibiotics.

Abstract

The emergence of bacterial multidrug resistance to antibiotics threatens to cause regression to the preantibiotic era. Here we present the crystal structure of the large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with the known antibiotics linezolid and telithromycin, as well as with a new, highly potent pleuromutilin derivative, BC-3205. These crystal structures shed light on specific structural motifs of the S. aureus ribosome and the binding modes of the aforementioned antibiotics. Moreover, by analyzing the ribosome structure and comparing it with those of nonpathogenic bacterial models, we identified some unique internal and peripheral structural motifs that may be potential candidates for improving known antibiotics and for use in the design of selective antibiotic drugs against S. aureus.

  • antibiotic resistance
  • potential advanced pleuoromutilin
  • species specificity
  • protein biosynthesis

Footnotes

  • ↵1Z.E. and D.M. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: ada.yonath{at}weizmann.ac.il.
  • Author contributions: A.B. and A.Y. designed research; Z.E., D.M., M.K., I.W., E.Z., H.R., and A.B. performed research; S.P. contributed new reagents/analytic tools; Z.E., D.M., M.K., I.W., E.Z., H.R., and A.B. analyzed data; and Z.E., D.M., A.B., and A.Y. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 4WCE, 4WFB, 4WF9, and 4WFA).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1517952112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Species specificity of a ribosome from a pathogen
Zohar Eyal, Donna Matzov, Miri Krupkin, Itai Wekselman, Susanne Paukner, Ella Zimmerman, Haim Rozenberg, Anat Bashan, Ada Yonath
Proceedings of the National Academy of Sciences Oct 2015, 112 (43) E5805-E5814; DOI: 10.1073/pnas.1517952112

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Species specificity of a ribosome from a pathogen
Zohar Eyal, Donna Matzov, Miri Krupkin, Itai Wekselman, Susanne Paukner, Ella Zimmerman, Haim Rozenberg, Anat Bashan, Ada Yonath
Proceedings of the National Academy of Sciences Oct 2015, 112 (43) E5805-E5814; DOI: 10.1073/pnas.1517952112
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Proceedings of the National Academy of Sciences: 112 (43)
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