Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutant

Yehuda Halfon; Donna Matzov; Zohar Eyal; Anat Bashan; Ella Zimmerman; Jette Kjeldgaard; Hanne Ingmer; Ada Yonath

doi:10.1038/s41598-019-48019-1

Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutant

Yehuda Halfon, Donna Matzov, Zohar Eyal, Anat Bashan, Ella Zimmerman, Jette Kjeldgaard, Hanne Ingmer, Ada Yonath^*

^*Corresponding author for this work

Department of Chemical and Structural Biology

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

The clinical use of the antibiotic erythromycin (ery) is hampered owing to the spread of resistance genes that are mostly mutating rRNA around the ery binding site at the entrance to the protein exit tunnel. Additional effective resistance mechanisms include deletion or insertion mutations in ribosomal protein uL22, which lead to alterations of the exit tunnel shape, located 16 angstrom away from the drug's binding site. We determined the cryo-EM structures of the Staphylococcus aureus 70S ribosome, and its ery bound complex with a two amino acid deletion mutation in its beta hairpin loop, which grants the bacteria resistance to ery. The structures reveal that, although the binding of ery is stable, the movement of the flexible shorter uL22 loop towards the tunnel wall creates a wider path for nascent proteins, thus enabling bypass of the barrier formed by the drug. Moreover, upon drug binding, the tunnel widens further.

Original language	English
Article number	11460
Number of pages	8
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-48019-1
Publication status	Published - 7 Aug 2019

Funding

We thank Shoshana Tel-Or, Miriam Lachever and Maggie Kessler for their interest and experimental support; We also thank Cristina Otero for critical reading. We acknowledge the European Synchrotron Radiation Facility for provision of microscope time on CM01 and we would like to thank Eaazhisai Kandiah for her assistance in the SAuL22m_apo project and to Michael Hons for is assistance in the SAuL22m_ery project. Funding was provided by European Research Council Grants 322581 (NOVRIB), the Kimmelman Center for Macromolecular Assemblies and the Danish National Research Foundation. A.Y. holds the Martin S. and Helen Kimmel Professorial Chair at the Weizmann Institute of Science. Author Contributions ; Y.H., A.B., E.Z., H.I. and A.Y. designed the research. Y.H., D.M., Z.E., E.Z. and J.K. performed the research; Y.H. and A.B. analyzed the data; Y.H., A.B. and A.Y. wrote the paper.

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abstract = "The clinical use of the antibiotic erythromycin (ery) is hampered owing to the spread of resistance genes that are mostly mutating rRNA around the ery binding site at the entrance to the protein exit tunnel. Additional effective resistance mechanisms include deletion or insertion mutations in ribosomal protein uL22, which lead to alterations of the exit tunnel shape, located 16 angstrom away from the drug's binding site. We determined the cryo-EM structures of the Staphylococcus aureus 70S ribosome, and its ery bound complex with a two amino acid deletion mutation in its beta hairpin loop, which grants the bacteria resistance to ery. The structures reveal that, although the binding of ery is stable, the movement of the flexible shorter uL22 loop towards the tunnel wall creates a wider path for nascent proteins, thus enabling bypass of the barrier formed by the drug. Moreover, upon drug binding, the tunnel widens further.",

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AU - Bashan, Anat

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AU - Kjeldgaard, Jette

AU - Ingmer, Hanne

AU - Yonath, Ada

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Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutant

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