Selective silencing of antibiotic-tethered ribosomes as a resistance mechanism against aminoglycosides
Antibiotic resistance is a growing threat, underscoring the need to understand the underlying mechanisms. Aminoglycosides kill bacteria by disrupting translation fidelity, leading to the synthesis of aberrant proteins. Surprisingly, mutations in fusA, a gene encoding translation elongation factor G (EF-G), frequently confer resistance, even though EF-G neither participates in mRNA decoding nor blocks aminoglycoside binding. Here, we show that EF-G resistance variants selectively slow ribosome movement along mRNA when aminoglycosides are bound. This delay increases the chance that the drug dissociates before misreading occurs. Over several elongation cycles, this selective silencing of drug-bound ribosomes prevents error cluster formation, preserving proteome and membrane integrity. As a result, fusA mutations confer resistance early in treatment by preventing self-promoted aminoglycoside uptake. Translation on drug-free ribosomes remains sufficiently rapid to sustain near-normal bacterial growth. The mechanism of selective silencing of corrupted targets reveals a previously unrecognized antibiotic resistance strategy with potential therapeutic implications.
Authors
- Antonio Z. Politi (ORCID: https://orcid.org/0000-0003-4788-0933)
- Christina Kothe
- Ana C. de A. P. Schwarzer (ORCID: https://orcid.org/0000-0001-6071-9584)
- Marina V. Rodnina (ORCID: https://orcid.org/0000-0003-0105-3879)
- Bee‐Zen Peng (ORCID: https://orcid.org/0000-0002-9832-8447)
- Valentyn Petrychenko (ORCID: https://orcid.org/0000-0001-9867-9493)
- N. Fischer (ORCID: https://orcid.org/0000-0002-4609-4052)
- Ekaterina Samatova (ORCID: https://orcid.org/0000-0001-7508-8076)
- Ingo Wohlgemuth (ORCID: https://orcid.org/0000-0001-9121-7675)
- Nicola S. Freyer (ORCID: https://orcid.org/0009-0006-6137-063X)
- Henning Urlaub (ORCID: https://orcid.org/0000-0003-1837-5233)
- Frank Peske (ORCID: https://orcid.org/0000-0003-3076-0409)
- Marlen Schmidt
- Nilanjan Ghosh Dastidar (ORCID: https://orcid.org/0000-0002-5290-7232)
Institutions
- Max Planck Institute for the Study of Religious and Ethnic Diversity (DE)
- Universitätsmedizin Göttingen (DE)
- Max Planck Institute for Mathematics (DE)
- Heidelberg Engineering (Germany) (DE)
- Max Planck Institute of Experimental Medicine (DE)
- Tissue Dynamics (Israel) (IL)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Göttingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s41467-025-65298-7
- Citations
- 1
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- Leibniz-Gemeinschaft