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 af dette arbejde

Sektion, Food Safety and Zoonoses

13 Citationer (Scopus)

14 Downloads (Pure)

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 Å 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 ß 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.

Originalsprog	Engelsk
Artikelnummer	11460
Tidsskrift	Scientific Reports
Vol/bind	9
Udgave nummer	1
Antal sider	8
ISSN	2045-2322
DOI	https://doi.org/10.1038/s41598-019-48019-1
Status	Udgivet - 2019

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10.1038/s41598-019-48019-1Licens: CC BY

Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutantForlagets udgivne version, 1,83 MBLicens: CC BY

Citationsformater

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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 {\AA} away from the drug{\textquoteright}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 {\ss} 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.",

author = "Yehuda Halfon and Donna Matzov and Zohar Eyal and Anat Bashan and Ella Zimmerman and Jette Kjeldgaard and Hanne Ingmer and Ada Yonath",

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T1 - Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutant

AU - Halfon, Yehuda

AU - Matzov, Donna

AU - Eyal, Zohar

AU - Bashan, Anat

AU - Zimmerman, Ella

AU - Kjeldgaard, Jette

AU - Ingmer, Hanne

AU - Yonath, Ada

PY - 2019

Y1 - 2019

N2 - 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 Å 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 ß 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.

AB - 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 Å 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 ß 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.

U2 - 10.1038/s41598-019-48019-1

DO - 10.1038/s41598-019-48019-1

M3 - Journal article

C2 - 31391518

AN - SCOPUS:85070353991

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

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ER -

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

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