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Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity

Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. M. tuberculosis is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and copper (Cu). However, M. tuberculosis with defective proteasome activity is highly sensit...

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Autores principales: Limón, Gina, Samhadaneh, Nora M., Pironti, Alejandro, Darwin, K. Heran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470581/
https://www.ncbi.nlm.nih.gov/pubmed/37350636
http://dx.doi.org/10.1128/mbio.00363-23
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author Limón, Gina
Samhadaneh, Nora M.
Pironti, Alejandro
Darwin, K. Heran
author_facet Limón, Gina
Samhadaneh, Nora M.
Pironti, Alejandro
Darwin, K. Heran
author_sort Limón, Gina
collection PubMed
description Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. M. tuberculosis is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and copper (Cu). However, M. tuberculosis with defective proteasome activity is highly sensitive to NO and Cu, making the proteasome an attractive target for drug development. Previous work linked NO susceptibility with the accumulation of para-hydroxybenzaldehyde (pHBA) in M. tuberculosis mutants with defective proteasomal degradation. In this study, we found that pHBA accumulation was also responsible for Cu sensitivity in these strains. We showed that exogenous addition of pHBA to wild-type M. tuberculosis cultures sensitized bacteria to Cu to a degree similar to that of a proteasomal degradation mutant. We determined that pHBA reduced the production and function of critical Cu resistance proteins of the regulated in copper repressor (RicR) regulon. Furthermore, we extended these Cu-sensitizing effects to an aldehyde that M. tuberculosis may face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can render M. tuberculosis susceptible to an existing host defense and could support a broader role for aldehydes in controlling M. tuberculosis infections. IMPORTANCE: M. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper, an established antibacterial metal used by immune cells to control M. tuberculosis and other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense.
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spelling pubmed-104705812023-09-01 Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity Limón, Gina Samhadaneh, Nora M. Pironti, Alejandro Darwin, K. Heran mBio Research Article Mycobacterium tuberculosis is a major human pathogen and the causative agent of tuberculosis disease. M. tuberculosis is able to persist in the face of host-derived antimicrobial molecules nitric oxide (NO) and copper (Cu). However, M. tuberculosis with defective proteasome activity is highly sensitive to NO and Cu, making the proteasome an attractive target for drug development. Previous work linked NO susceptibility with the accumulation of para-hydroxybenzaldehyde (pHBA) in M. tuberculosis mutants with defective proteasomal degradation. In this study, we found that pHBA accumulation was also responsible for Cu sensitivity in these strains. We showed that exogenous addition of pHBA to wild-type M. tuberculosis cultures sensitized bacteria to Cu to a degree similar to that of a proteasomal degradation mutant. We determined that pHBA reduced the production and function of critical Cu resistance proteins of the regulated in copper repressor (RicR) regulon. Furthermore, we extended these Cu-sensitizing effects to an aldehyde that M. tuberculosis may face within the macrophage. Collectively, this study is the first to mechanistically propose how aldehydes can render M. tuberculosis susceptible to an existing host defense and could support a broader role for aldehydes in controlling M. tuberculosis infections. IMPORTANCE: M. tuberculosis is a leading cause of death by a single infectious agent, causing 1.5 million deaths annually. An effective vaccine for M. tuberculosis infections is currently lacking, and prior infection does not typically provide robust immunity to subsequent infections. Nonetheless, immunocompetent humans can control M. tuberculosis infections for decades. For these reasons, a clear understanding of how mammalian immunity inhibits mycobacterial growth is warranted. In this study, we show aldehydes can increase M. tuberculosis susceptibility to copper, an established antibacterial metal used by immune cells to control M. tuberculosis and other microbes. Given that activated macrophages produce increased amounts of aldehydes during infection, we propose host-derived aldehydes may help control bacterial infections, making aldehydes a previously unappreciated antimicrobial defense. American Society for Microbiology 2023-06-23 /pmc/articles/PMC10470581/ /pubmed/37350636 http://dx.doi.org/10.1128/mbio.00363-23 Text en Copyright © 2023 Limón 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
Limón, Gina
Samhadaneh, Nora M.
Pironti, Alejandro
Darwin, K. Heran
Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
title Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
title_full Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
title_fullStr Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
title_full_unstemmed Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
title_short Aldehyde accumulation in Mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
title_sort aldehyde accumulation in mycobacterium tuberculosis with defective proteasomal degradation results in copper sensitivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470581/
https://www.ncbi.nlm.nih.gov/pubmed/37350636
http://dx.doi.org/10.1128/mbio.00363-23
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