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Mechanism of fusidic acid inhibition of RRF- and EF-G-dependent splitting of the bacterial post-termination ribosome
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
2016 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no 7, 3264-3275 p.Article in journal (Refereed) Published
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Abstract [en]

The antibiotic drug fusidic acid (FA) is commonly used in the clinic against gram-positive bacterial infections. FA targets ribosome-bound elongation factor G (EF-G), a translational GTPase that accelerates both messenger RNA (mRNA) translocation and ribosome recycling. How FA inhibits translocation was recently clarified, but FA inhibition of ribosome recycling by EF-G and ribosome recycling factor (RRF) has remained obscure. Here we use fast kinetics techniques to estimate mean times of ribosome splitting and the stoichiometry of GTP hydrolysis by EF-G at varying concentrations of FA, EF-G and RRF. These mean times together with previous data on uninhibited ribosome recycling were used to clarify the mechanism of FA inhibition of ribosome splitting. The biochemical data on FA inhibition of translocation and recycling were used to model the growth inhibitory effect of FA on bacterial populations. We conclude that FA inhibition of translocation provides the dominant cause of bacterial growth reduction, but that FA inhibition of ribosome recycling may contribute significantly to FA-induced expression of short regulatory open reading frames, like those involved in FA resistance.

Place, publisher, year, edition, pages
2016. Vol. 44, no 7, 3264-3275 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-297902DOI: 10.1093/nar/gkw178ISI: 000375800200033PubMedID: 27001509OAI: oai:DiVA.org:uu-297902DiVA: diva2:944372
Funder
Swedish Research Council, 2015-04682Knut and Alice Wallenberg Foundation, KAW 2009.0251
Available from: 2016-06-29 Created: 2016-06-28 Last updated: 2017-11-28Bibliographically approved

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Pavlov, MichaelEhrenberg, Måns

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