The cyclic octapeptide antibiotic argyrin B inhibits translation by trapping EF-G on the ribosome during translocation

Argyrins are a family of naturally produced octapeptides that display promising antimicrobial activity against Pseudomonas aeruginosa. Argyrin B (ArgB) has been shown to interact with an elongated form of the translation elongation factor G (EF-G), leading to the suggestion that argyrins inhibit pro...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-05, Vol.119 (19), p.e2114214119
Main Authors: Wieland, Maximiliane, Holm, Mikael, Rundlet, Emily J, Morici, Martino, Koller, Timm O, Maviza, Tinashe P, Pogorevc, Domen, Osterman, Ilya A, Müller, Rolf, Blanchard, Scott C, Wilson, Daniel N
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - metabolism
Antibiotics
Antiinfectives and antibacterials
Antimicrobial activity
Binding
Biological Sciences
Electron microscopy
Elongation
Energy transfer
Fluorescence
Fluorescence resonance energy transfer
Fusidic acid
Fusidic Acid - pharmacology
Humans
Octapeptides
Oligopeptides
Peptide Elongation Factor G - metabolism
Protein biosynthesis
Protein synthesis
Proteins
Pseudomonas aeruginosa
Ribosomes - metabolism
Translation
Translation elongation
Translocation
Translocation, Genetic
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Summary:Argyrins are a family of naturally produced octapeptides that display promising antimicrobial activity against Pseudomonas aeruginosa. Argyrin B (ArgB) has been shown to interact with an elongated form of the translation elongation factor G (EF-G), leading to the suggestion that argyrins inhibit protein synthesis by interfering with EF-G binding to the ribosome. Here, using a combination of cryo-electron microscopy (cryo-EM) and single-molecule fluorescence resonance energy transfer (smFRET), we demonstrate that rather than interfering with ribosome binding, ArgB rapidly and specifically binds EF-G on the ribosome to inhibit intermediate steps of the translocation mechanism. Our data support that ArgB inhibits conformational changes within EF-G after GTP hydrolysis required for translocation and factor dissociation, analogous to the mechanism of fusidic acid, a chemically distinct antibiotic that binds a different region of EF-G. These findings shed light on the mechanism of action of the argyrin-class antibiotics on protein synthesis as well as the nature and importance of rate-limiting, intramolecular conformational events within the EF-G-bound ribosome during late-steps of translocation.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2114214119