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PLoS Pathog DOI:10.1371/journal.ppat.1003946

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

Publication TypeJournal Article
Year of Publication2014
AuthorsStanley, SA, Barczak, AK, Silvis, MR, Luo, SS, Sogi, K, Vokes, M, Bray, M-A, Carpenter, AE, Moore, CB, Siddiqi, N, Rubin, EJ, Hung, DT
JournalPLoS Pathog
Date Published2014 Feb
KeywordsAnimals, Antitubercular Agents, Disease Models, Animal, High-Throughput Screening Assays, Host-Pathogen Interactions, Macrophages, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mycobacterium tuberculosis, Signal Transduction, Tuberculosis

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.


Alternate JournalPLoS Pathog.
PubMed ID24586159
PubMed Central IDPMC3930586
Grant ListK08 AI080944 / AI / NIAID NIH HHS / United States
R01 GM089652 / GM / NIGMS NIH HHS / United States