Selective silencing of antibiotic-tethered ribosomes as a resistance mechanism against aminoglycosides

Nilanjan Ghosh Dastidar, Nicola S. Freyer, Valentyn Petrychenko, Ana C. A. P. Schwarzer, Bee-Zen Peng, Ekaterina Samatova, Christina Kothe, Marlen Schmidt, Frank Peske, Antonio Z. Politi, Henning Urlaub, Niels Fischer, Marina V. Rodnina () and Ingo Wohlgemuth ()
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Nilanjan Ghosh Dastidar: Max Planck Institute for Multidisciplinary Sciences
Nicola S. Freyer: Max Planck Institute for Multidisciplinary Sciences
Valentyn Petrychenko: Max Planck Institute for Multidisciplinary Sciences
Ana C. A. P. Schwarzer: Max Planck Institute for Multidisciplinary Sciences
Bee-Zen Peng: Max Planck Institute for Multidisciplinary Sciences
Ekaterina Samatova: Max Planck Institute for Multidisciplinary Sciences
Christina Kothe: Max Planck Institute for Multidisciplinary Sciences
Marlen Schmidt: Genetic Engineering Heidelberg GmbH
Frank Peske: Max Planck Institute for Multidisciplinary Sciences
Antonio Z. Politi: Max Planck Institute for Multidisciplinary Sciences
Henning Urlaub: Max Planck Institute for Multidisciplinary Sciences
Niels Fischer: Max Planck Institute for Multidisciplinary Sciences
Marina V. Rodnina: Max Planck Institute for Multidisciplinary Sciences
Ingo Wohlgemuth: Max Planck Institute for Multidisciplinary Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65298-7

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