Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.

Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if app...

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Autores principales: Sarah A Stanley, Amy K Barczak, Melanie R Silvis, Samantha S Luo, Kimberly Sogi, Martha Vokes, Mark-Anthony Bray, Anne E Carpenter, Christopher B Moore, Noman Siddiqi, Eric J Rubin, Deborah T Hung
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Publicado: Public Library of Science (PLoS) 2014
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Acceso en línea:https://doaj.org/article/5b406ec88de142fa943bed895dc1f3bd
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spelling oai:doaj.org-article:5b406ec88de142fa943bed895dc1f3bd2021-11-18T06:06:58ZIdentification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.1553-73661553-737410.1371/journal.ppat.1003946https://doaj.org/article/5b406ec88de142fa943bed895dc1f3bd2014-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24586159/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated. The outcome of infection is determined at least in part by the host-pathogen interaction within the macrophage; however, we lack a complete understanding of which host pathways are critical for bacterial survival and replication. To add to our understanding of the molecular processes involved in intracellular infection, we performed a chemical screen using a high-content microscopic assay to identify small molecules that restrict mycobacterial growth in macrophages by targeting host functions and pathways. The identified host-targeted inhibitors restrict bacterial growth exclusively in the context of macrophage infection and predominantly fall into five categories: G-protein coupled receptor modulators, ion channel inhibitors, membrane transport proteins, anti-inflammatories, and kinase modulators. We found that fluoxetine, a selective serotonin reuptake inhibitor, enhances secretion of pro-inflammatory cytokine TNF-α and induces autophagy in infected macrophages, and gefitinib, an inhibitor of the Epidermal Growth Factor Receptor (EGFR), also activates autophagy and restricts growth. We demonstrate that during infection signaling through EGFR activates a p38 MAPK signaling pathway that prevents macrophages from effectively responding to infection. Inhibition of this pathway using gefitinib during in vivo infection reduces growth of M. tuberculosis in the lungs of infected mice. Our results support the concept that screening for inhibitors using intracellular models results in the identification of tool compounds for probing pathways during in vivo infection and may also result in the identification of new anti-tuberculosis agents that work by modulating host pathways. Given the existing experience with some of our identified compounds for other therapeutic indications, further clinically-directed study of these compounds is merited.Sarah A StanleyAmy K BarczakMelanie R SilvisSamantha S LuoKimberly SogiMartha VokesMark-Anthony BrayAnne E CarpenterChristopher B MooreNoman SiddiqiEric J RubinDeborah T HungPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 2, p e1003946 (2014)
institution DOAJ
collection DOAJ
language EN
topic Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
spellingShingle Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
Sarah A Stanley
Amy K Barczak
Melanie R Silvis
Samantha S Luo
Kimberly Sogi
Martha Vokes
Mark-Anthony Bray
Anne E Carpenter
Christopher B Moore
Noman Siddiqi
Eric J Rubin
Deborah T Hung
Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.
description Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated. The outcome of infection is determined at least in part by the host-pathogen interaction within the macrophage; however, we lack a complete understanding of which host pathways are critical for bacterial survival and replication. To add to our understanding of the molecular processes involved in intracellular infection, we performed a chemical screen using a high-content microscopic assay to identify small molecules that restrict mycobacterial growth in macrophages by targeting host functions and pathways. The identified host-targeted inhibitors restrict bacterial growth exclusively in the context of macrophage infection and predominantly fall into five categories: G-protein coupled receptor modulators, ion channel inhibitors, membrane transport proteins, anti-inflammatories, and kinase modulators. We found that fluoxetine, a selective serotonin reuptake inhibitor, enhances secretion of pro-inflammatory cytokine TNF-α and induces autophagy in infected macrophages, and gefitinib, an inhibitor of the Epidermal Growth Factor Receptor (EGFR), also activates autophagy and restricts growth. We demonstrate that during infection signaling through EGFR activates a p38 MAPK signaling pathway that prevents macrophages from effectively responding to infection. Inhibition of this pathway using gefitinib during in vivo infection reduces growth of M. tuberculosis in the lungs of infected mice. Our results support the concept that screening for inhibitors using intracellular models results in the identification of tool compounds for probing pathways during in vivo infection and may also result in the identification of new anti-tuberculosis agents that work by modulating host pathways. Given the existing experience with some of our identified compounds for other therapeutic indications, further clinically-directed study of these compounds is merited.
format article
author Sarah A Stanley
Amy K Barczak
Melanie R Silvis
Samantha S Luo
Kimberly Sogi
Martha Vokes
Mark-Anthony Bray
Anne E Carpenter
Christopher B Moore
Noman Siddiqi
Eric J Rubin
Deborah T Hung
author_facet Sarah A Stanley
Amy K Barczak
Melanie R Silvis
Samantha S Luo
Kimberly Sogi
Martha Vokes
Mark-Anthony Bray
Anne E Carpenter
Christopher B Moore
Noman Siddiqi
Eric J Rubin
Deborah T Hung
author_sort Sarah A Stanley
title Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.
title_short Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.
title_full Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.
title_fullStr Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.
title_full_unstemmed Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.
title_sort identification of host-targeted small molecules that restrict intracellular mycobacterium tuberculosis growth.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/5b406ec88de142fa943bed895dc1f3bd
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