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Cited by 5RNA and protein synthesis mechanismsAntibiotic Resistance in BacteriaBacterial Genetics and Biotechnology

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Structural mechanism of FusB-mediated rescue from fusidic acid inhibition of protein synthesis

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González-López, Adrián, Ge, Xueliang, Larsson, Daniel S. D., Sihlbom Wallem, Carina, Sanyal, Suparna, Selmer, Maria·2025·Nature Communications
DOI 10.1038/s41467-025-58902-3PMC PMC12008383

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Abstract

The antibiotic resistance protein FusB rescues protein synthesis from inhibition by fusidic acid (FA), which locks elongation factor G (EF-G) to the ribosome after GTP hydrolysis. Here, we present time-resolved single–particle cryo-EM structures explaining the mechanism of FusB-mediated rescue. FusB binds to the FA-trapped EF-G on the ribosome, causing large-scale conformational changes of EF-G that break interactions with the ribosome, tRNA, and mRNA. This leads to dissociation of EF-G from the ribosome, followed by FA release. We also observe two independent binding sites of FusB on the classical-state ribosome, overlapping with the binding site of EF-G to each of the ribosomal subunits, yet not inhibiting tRNA delivery. The affinity of FusB to the ribosome and the concentration of FusB in S. aureus during FusB-mediated resistance support that direct binding of FusB to ribosomes could occur in the cell. Our results reveal an intricate resistance mechanism involving specific interactions of FusB with both EF-G and the ribosome, and a non-canonical release pathway of EF-G.

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Metadata

Authors
González-López, A., Ge, X., Larsson, D. S. D., Sihlbom Wallem, C., Sanyal, S., & Selmer, M.
Affiliations
Uppsala University (SE)
Corresponding author
Selmer, Maria
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-04-18
Volume
16
Issue
1
Pages
3693-3693
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-58902-3
PMC
PMC12008383
OpenAlex
W4409587725
Cited by
5
References
2
Citations by year
2026: 4 · 2025: 1
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Vetenskapsrådet (2016-06264, 2017-03827, 2022-04511, 2018-05946)
  • Knut och Alice Wallenbergs Stiftelse (KAW 2017.0055)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
fusidic acid, antibiotic resistance, elongation factor G, ribosome, protein synthesis inhibition, Staphylococcus aureus, ribosome conformational change, ribosome binding site, time-resolved cryo-EM
MeSH terms
Anti-Bacterial Agents, Bacterial Proteins, Binding Sites, Fusidic Acid, Guanosine Triphosphate, Protein Binding, Ribosomes, RNA, Messenger, RNA, Transfer, Staphylococcus aureus, Protein Biosynthesis, Cryoelectron Microscopy, Peptide Elongation Factor G, Drug Resistance, Bacterial

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