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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Escherichia Coli

SUBMITTER: Ingo Wohlgemuth

LAB HEAD: Dr Ingo Wohlgemuth

PROVIDER: PXD061583 | Pride | 2025-08-28

REPOSITORIES: Pride

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			Action	DRS
	File_description.xlsx	Xlsx
	NDastidar_IW_290323_010423_Expl4_Ecoli_DIA_A608E_logOD_brep1.raw	Raw
	NDastidar_IW_290323_010423_Expl4_Ecoli_DIA_A608E_logOD_brep1_trep2.raw	Raw
	NDastidar_IW_290323_010423_Expl4_Ecoli_DIA_A608E_logOD_brep2.raw	Raw
	NDastidar_IW_290323_010423_Expl4_Ecoli_DIA_A608E_logOD_brep2_trep2.raw	Raw

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Project description:The ability to eliminate bacterial persister cells is still a medical challenge that has yet to be overcome. These cells represent a unique subpopulation within bacterial communities and are characterized by a reduced susceptibility to antibiotics with growth retardation. In this study, we investigated the molecular basis of persister formation in Salmonella Typhimurium 14028s under aminoglycoside stress.We analyzed the crystal structure of the STM14_5441–STM14_5442 complex, which belongs to the type II toxin-antitoxin system, and identified key ribosome binding residues in STM14_5441. Changes in the antibiotic susceptibility of Salmonella caused by the loss of the ribosome binding property of STM14_5441 were assessed. We conducted intracellular ATP assays under aminoglycoside stress and RNA-seq analysis following STM14_5441 induction.Our studies demonstrated the critical role of STM14_5441 in the formation of persister cells in Salmonella, particularly those under aminoglycoside stress. We observed that a loss of ribosome binding in STM14_5441 resulted in increased antibiotic susceptibility. Additionally, intracellular ATP assays revealed increased ATP levels in bacterial persister cells, and RNA-seq analysis identified several genes that play a role in the formation of these persister cells.The present data suggest that persister forms under aminoglycoside stress through the following mechanisms: i) inhibition of membrane hyperpolarization by impeding F1Fo ATP synthase activity and ii) enhanced poststress recovery by ATP storage and increased protein synthesis capacity. Based on this suggestion, we reannotated the STM14_5441-STM14_5442 TA pair as the ResTA (RNA cleavage-induced energy storage toxin-antitoxin) system. Furthermore, new insights into the function of TA systems may lay the groundwork for developing novel strategies to target bacterial persister cells, thereby preventing the accelerated emergence of antibiotic resistance in bacterial populations.

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

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