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

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 aminoglycoside is 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 clusters 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. This previously unrecognized resistance mechanism—selective silencing of corrupted targets—reveals a novel antibiotic resistance strategy with potential therapeutic implications.

ORGANISM(S): Escherichia Coli K-12

SUBMITTER: Ingo Wohlgemuth

PROVIDER: PXD063129 | panorama | Fri Aug 29 00:00:00 BST 2025

REPOSITORIES: PanoramaPublic

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

Project description: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.

2025-09-05 | PXD067947 | Pride

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

Project description:Understanding antibiotic resistance is essential for combating drug-resistant pathogens. Many bacteria horizontally acquire enzymes that modify antibiotics or their targets to prevent interaction, but when resistance emerges without such modifications, the underlying mechanisms often remain unknown. Here, we describe how mutations in the fusA gene, which encodes translation elongation factor G (EF-G), drive resistance against aminoglycoside antibiotics. fusA resistance mutations, found throughout EF-G, confer resistance without disrupting AGA binding to the ribosome. EF-G resistance variants selectively slow down translocation on aminoglycoside-bound ribosomes until the drug dissociates. This slowdown prevents antibiotic-induced incorporation of consecutive incorrect amino acids (error clusters) into proteins, preserving the proteome and membrane integrity, and limiting drug uptake. In contrast, translocation on antibiotic-free ribosomes remains sufficiently rapid to support near-normal cell growth with or without antibiotic. This previously unrecognized resistance concept—selective silencing of corrupted targets—offers new insights into antibiotic resistance mechanisms beyond traditional paradigms.

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