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tRNA methylation: An unexpected link to bacterial resistance and persistence to antibiotics and beyond

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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 m1G37 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 m1G37‐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 m1G37‐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
The Gram‐negative cell envelope, consisting of an outer membrane (OM), an inner membrane (IM), and a thin peptidoglycan layer within the periplasmic space between the two membranes. The OM is an asymmetric phospholipid bilayer, with the outer leaflet modified by lipopolysaccharides (LPSs) that form the core structure for the permeability barrier and with the inner leaflet made up of phospholipids. Multiple porin proteins are embedded in the OM, functioning as channels for transport of nutrients and metabolites. The IM is a symmetric phospholipid bilayer that anchors proteins of electron transport chain complexes (e.g., NADH dehydrogenase complex, cytochrome bc1 complex, and cytochrome oxidase complex), and FOF1 adenosine triphosphate (ATP) synthase for generation of ATP. The major drug efflux AcrAB–TolC complex consists of the proton‐dependent AcrB pump located at the IM, the channel protein TolC at the OM, and the bridging AcrA protein
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Control of biosynthesis of Gram‐negative cell envelope by the TrmD‐catalyzed m1G37‐tRNA. (a) Mechanisms of action of antibiotics that become more potent in Escherichia coli and Salmonella cells deficient of TrmD. These antibiotics are categorized into five mechanisms: (1) inhibition of bacterial cell wall synthesis, (2) inhibition of DNA replication, (3) inhibition of mRNA synthesis, (4) inhibition of protein synthesis on the ribosome, and (5) disruption of bacterial membranes. In all cases, the MIC value of each antibiotic decreases in trmD‐KD cells relative to trmD‐WT cells. (b) E. coli and Salmonella trmD‐WT cells have an active cell‐envelope structure, due to the ability to synthesize m1G37‐tRNA for translation of membrane‐associated genes containing Pro codons, and are thus resistant to antibiotics via the action of the membrane permeability barrier and efflux pumps. (c) E. coli and Salmonella trmD‐KD cells have a defective cell envelope, due to the deficiency of m1G37 and the inability to translate membrane‐associated genes containing Pro codons, and are thus sensitive to antibiotic killing
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The increase and decrease of inner‐membrane (IM) proteins in Escherichia coli cells deficient of m1G37‐tRNA. The increase (denoted by +) or decrease (denoted by –) in protein abundance in m1G37 deficiency relative to control is indicated by a filled circle at the respective column. Genes are categorized by functions
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The increase and decrease of outer‐membrane (OM) proteins in Escherichia coli cells deficient of m1G37‐tRNA. The increase (denoted by +) or decrease (denoted by –) in protein abundance in m1G37 deficiency relative to control is indicated by a filled circle the at the respective column. Genes are categorized by annotations
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Membrane‐associated genes with Pro codons near the initiation AUG codon in Vibrio cholerae, Haemophilus influenzae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The gene sequences are retrieved and presented as in Figure 2. For Pseudomonas, genes with three consecutive Pro codons around 30th to 40th position are also shown. The strain for each species is: V. cholerae O1 El Tor N16961, H. influenzae Rd KW20, A. baumannii ATCC 17978, and P. aeruginosa PAO1 and PA7
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Membrane‐associated genes with Pro codons near the initiation AUG codon in Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, Enterobacter cloaceae, Shigella flexneri, and Yersinia pestis. CC[C/U] codons are shown in red and CC[G/A] codons are in blue. Sequences and descriptions for each gene are retrieved from KEGG GENOME database (https://www.genome.jp/kegg/genome.html) or UniProt (https://www.uniprot.org/). The strain and abbreviation (in parentheses) for each species are: E. coli K‐12 MG1655 (Eco), S. enterica ssp. enterica serovar Typhimurium LT2 (Sen), K. pneumoniae subsp. pneumoniae MGH 78578 (Kpn), E. cloacae subsp. cloacae ATCC 13047 (Ecl), S. flexneri 301 (serotype 2a) (Sfl) Y. pestis CO92 (biovar Orientalis) (Ype). As indicated by an *, mdtG sequences for Shigella and Yersinia were from Shigella sp. and Y. frederiksenii, respectively
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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Processing > RNA Editing and Modification
Translation > Translation Regulation

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