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

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

*Corresponding author for this work

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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 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.
Original languageEnglish
Article number11460
JournalScientific Reports
Volume9
Issue number1
Number of pages8
ISSN2045-2322
DOIs
Publication statusPublished - 2019

Cite this

Halfon, Y., Matzov, D., Eyal, Z., Bashan, A., Zimmerman, E., Kjeldgaard, J. S., Ingmer, H., & Yonath, A. (2019). Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutant. Scientific Reports, 9(1), [11460]. https://doi.org/10.1038/s41598-019-48019-1