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tRNA methylation: An unexpected link to bacterial resistance and persistence to antibiotics and beyond
Ya-Ming Hou1, Isao Masuda1, Leonard J Foster2
1Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract:
A major threat to public health is the resistance and persistence of Gram-negative bacteria to multiple drugs during antibiotic treatment. The resistance is due to the ability of these bacteria to block antibiotics from permeating into and accumulating inside the cell, while the persistence is due to the ability of these bacteria to enter into a nonreplicating state that shuts down major metabolic pathways but remains active in drug efflux. Resistance and persistence are permitted by the unique cell envelope structure of Gram-negative bacteria, which consists of both an outer and an inner membrane (OM and IM, respectively) that lay above and below the cell wall. Unexpectedly, recent work reveals that m1 G37 methylation of tRNA, at the N1 of guanosine at position 37 on the 3'-side of the tRNA anticodon, controls biosynthesis of both membranes and determines the integrity of cell envelope structure, thus providing a novel link to the development of bacterial resistance and persistence to antibiotics. The impact of m1 G37-tRNA methylation on Gram-negative bacteria can reach further, by determining the ability of these bacteria to exit from the persistence state when the antibiotic treatment is removed. These conceptual advances raise the possibility that successful targeting of m1 G37-tRNA methylation can provide new approaches for treating acute and chronic infections caused by Gram-negative bacteria. This article is categorized under: Translation > Translation Regulation RNA Processing > RNA Editing and Modification RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.
Insights
Gram-negative bacteria resist antibiotics via complex cell envelopes. Targeting m1G37 tRNA methylation offers a novel strategy against drug-resistant infections by controlling cell envelope integrity and bacterial persistence.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Discovery
Background:
- Gram-negative bacteria pose a significant public health threat due to their multidrug resistance and persistence.
- Bacterial resistance and persistence are facilitated by the unique cell envelope structure, including outer and inner membranes.
- These bacteria can enter a non-replicating state, shutting down metabolic pathways while maintaining drug efflux.
Purpose of the Study:
- To investigate the role of m1G37 methylation of transfer RNA (tRNA) in Gram-negative bacteria.
- To explore the link between m1G37-tRNA methylation, cell envelope integrity, and antibiotic resistance/persistence.
- To assess the potential of targeting m1G37-tRNA methylation as a therapeutic strategy.
Main Methods:
- Analysis of m1G37 methylation patterns in Gram-negative bacteria.
- Investigating the impact of m1G37-tRNA methylation on cell envelope biosynthesis and structure.
- Assessing the influence of m1G37-tRNA methylation on bacterial persistence and exit from this state.
Main Results:
- m1G37 methylation of tRNA unexpectedly controls the biosynthesis of both cell membranes in Gram-negative bacteria.
- This methylation is crucial for maintaining the integrity of the bacterial cell envelope.
- m1G37-tRNA methylation influences bacterial persistence and the ability to exit this state upon removal of antibiotic treatment.
Conclusions:
- m1G37-tRNA methylation represents a novel link to antibiotic resistance and persistence in Gram-negative bacteria.
- Targeting m1G37-tRNA methylation could offer new therapeutic approaches for infections caused by these pathogens.
- Understanding this mechanism provides insights into bacterial survival strategies and potential vulnerabilities.
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