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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-02-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24586159/?tool=EBI |
| _version_ | 1819101460330184704 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-22T01:19:01Z |
| format | Article |
| id | doaj.art-5b406ec88de142fa943bed895dc1f3bd |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-22T01:19:01Z |
| publishDate | 2014-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-5b406ec88de142fa943bed895dc1f3bd2022-12-21T18:43:46ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-02-01102e100394610.1371/journal.ppat.1003946Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth.Sarah A StanleyAmy K BarczakMelanie R SilvisSamantha S LuoKimberly SogiMartha VokesMark-Anthony BrayAnne E CarpenterChristopher B MooreNoman SiddiqiEric J RubinDeborah T HungMycobacterium 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24586159/?tool=EBI |
| spellingShingle | 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. PLoS Pathogens |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24586159/?tool=EBI |
| work_keys_str_mv | AT sarahastanley identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT amykbarczak identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT melaniersilvis identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT samanthasluo identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT kimberlysogi identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT marthavokes identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT markanthonybray identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT anneecarpenter identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT christopherbmoore identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT nomansiddiqi identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT ericjrubin identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth AT deborahthung identificationofhosttargetedsmallmoleculesthatrestrictintracellularmycobacteriumtuberculosisgrowth |