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The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection
Successful pathogens must be able to adapt to a multitude of stressors imposed by their host. Acinetobacter baumannii has emerged as a major global health threat due to its exceptional ability to adapt to hostile environments and skyrocketing rates of multidrug resistance. Recent studies have begun...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653896/ https://www.ncbi.nlm.nih.gov/pubmed/37589464 http://dx.doi.org/10.1128/mbio.01416-23 |
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author | McGuffey, Jenna C. Jackson-Litteken, Clay D. Di Venanzio, Gisela Zimmer, Aubree A. Lewis, Jessica M. Distel, Jesus S. Kim, Kyusik Q. Zaher, Hani S. Alfonzo, Juan Scott, Nichollas E. Feldman, Mario F. |
author_facet | McGuffey, Jenna C. Jackson-Litteken, Clay D. Di Venanzio, Gisela Zimmer, Aubree A. Lewis, Jessica M. Distel, Jesus S. Kim, Kyusik Q. Zaher, Hani S. Alfonzo, Juan Scott, Nichollas E. Feldman, Mario F. |
author_sort | McGuffey, Jenna C. |
collection | PubMed |
description | Successful pathogens must be able to adapt to a multitude of stressors imposed by their host. Acinetobacter baumannii has emerged as a major global health threat due to its exceptional ability to adapt to hostile environments and skyrocketing rates of multidrug resistance. Recent studies have begun to explore the importance of tRNA methylation in the regulation of bacterial stress responses, including adaptation to antibiotic and oxidative stresses. However, tRNA methyltransferases (trms) have not been investigated in A. baumannii. Bioinformatic analyses revealed nine putative, SAM-dependent trms conserved across clinical A. baumannii isolates and laboratory strains. We generated eight trm mutants in a modern, colistin-resistant clinical isolate, ARC6851, and analyzed the mutants’ stress responses. One mutant, ΔtrmB, was vastly more sensitive to oxidative stress and displayed a growth defect at low pH. Accordingly, ΔtrmB was unable to replicate in J774A.1 macrophages and had decreased virulence in an acute pneumonia murine model. Subsequently, we showed that A. baumannii TrmB makes the m(7)G tRNA modification. A proteomic analysis revealed that ARC6851 significantly upregulates a siderophore biosynthesis and uptake cluster, acinetobactin, under oxidative stress. In contrast, the upregulation of the acinetobactin proteins in ΔtrmB was only modest, which impacted its ability to withstand iron deprivation under oxidative stress. qRT-PCR data showed that TrmB-dependent regulation of acinetobactin is post-transcriptional. Our results indicate that TrmB-mediated stress responses are important for A. baumannii pathogenesis, highlighting the therapeutic potential of targeting trms to combat the rise of multidrug-resistant A. baumannii. IMPORTANCE: As deficiencies in tRNA modifications have been linked to human diseases such as cancer and diabetes, much research has focused on the modifications’ impacts on translational regulation in eukaryotes. However, the significance of tRNA modifications in bacterial physiology remains largely unexplored. In this paper, we demonstrate that the m(7)G tRNA methyltransferase TrmB is crucial for a top-priority pathogen, Acinetobacter baumannii, to respond to stressors encountered during infection, including oxidative stress, low pH, and iron deprivation. We show that loss of TrmB dramatically attenuates a murine pulmonary infection. Given the current efforts to use another tRNA methyltransferase, TrmD, as an antimicrobial therapeutic target, we propose that TrmB, and other tRNA methyltransferases, may also be viable options for drug development to combat multidrug-resistant A. baumannii. |
format | Online Article Text |
id | pubmed-10653896 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-106538962023-08-17 The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection McGuffey, Jenna C. Jackson-Litteken, Clay D. Di Venanzio, Gisela Zimmer, Aubree A. Lewis, Jessica M. Distel, Jesus S. Kim, Kyusik Q. Zaher, Hani S. Alfonzo, Juan Scott, Nichollas E. Feldman, Mario F. mBio Research Article Successful pathogens must be able to adapt to a multitude of stressors imposed by their host. Acinetobacter baumannii has emerged as a major global health threat due to its exceptional ability to adapt to hostile environments and skyrocketing rates of multidrug resistance. Recent studies have begun to explore the importance of tRNA methylation in the regulation of bacterial stress responses, including adaptation to antibiotic and oxidative stresses. However, tRNA methyltransferases (trms) have not been investigated in A. baumannii. Bioinformatic analyses revealed nine putative, SAM-dependent trms conserved across clinical A. baumannii isolates and laboratory strains. We generated eight trm mutants in a modern, colistin-resistant clinical isolate, ARC6851, and analyzed the mutants’ stress responses. One mutant, ΔtrmB, was vastly more sensitive to oxidative stress and displayed a growth defect at low pH. Accordingly, ΔtrmB was unable to replicate in J774A.1 macrophages and had decreased virulence in an acute pneumonia murine model. Subsequently, we showed that A. baumannii TrmB makes the m(7)G tRNA modification. A proteomic analysis revealed that ARC6851 significantly upregulates a siderophore biosynthesis and uptake cluster, acinetobactin, under oxidative stress. In contrast, the upregulation of the acinetobactin proteins in ΔtrmB was only modest, which impacted its ability to withstand iron deprivation under oxidative stress. qRT-PCR data showed that TrmB-dependent regulation of acinetobactin is post-transcriptional. Our results indicate that TrmB-mediated stress responses are important for A. baumannii pathogenesis, highlighting the therapeutic potential of targeting trms to combat the rise of multidrug-resistant A. baumannii. IMPORTANCE: As deficiencies in tRNA modifications have been linked to human diseases such as cancer and diabetes, much research has focused on the modifications’ impacts on translational regulation in eukaryotes. However, the significance of tRNA modifications in bacterial physiology remains largely unexplored. In this paper, we demonstrate that the m(7)G tRNA methyltransferase TrmB is crucial for a top-priority pathogen, Acinetobacter baumannii, to respond to stressors encountered during infection, including oxidative stress, low pH, and iron deprivation. We show that loss of TrmB dramatically attenuates a murine pulmonary infection. Given the current efforts to use another tRNA methyltransferase, TrmD, as an antimicrobial therapeutic target, we propose that TrmB, and other tRNA methyltransferases, may also be viable options for drug development to combat multidrug-resistant A. baumannii. American Society for Microbiology 2023-08-17 /pmc/articles/PMC10653896/ /pubmed/37589464 http://dx.doi.org/10.1128/mbio.01416-23 Text en Copyright © 2023 McGuffey et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article McGuffey, Jenna C. Jackson-Litteken, Clay D. Di Venanzio, Gisela Zimmer, Aubree A. Lewis, Jessica M. Distel, Jesus S. Kim, Kyusik Q. Zaher, Hani S. Alfonzo, Juan Scott, Nichollas E. Feldman, Mario F. The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection |
title | The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection |
title_full | The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection |
title_fullStr | The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection |
title_full_unstemmed | The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection |
title_short | The tRNA methyltransferase TrmB is critical for Acinetobacter baumannii stress responses and pulmonary infection |
title_sort | trna methyltransferase trmb is critical for acinetobacter baumannii stress responses and pulmonary infection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653896/ https://www.ncbi.nlm.nih.gov/pubmed/37589464 http://dx.doi.org/10.1128/mbio.01416-23 |
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