The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Identification of Host-Targeted Small Molecules That Restrict Intracellular Mycobacterium tuberculosis Growth
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Specifically, fluoxetine, a selective serotoine re-uptake inhibitor, and gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) activity stimulated autophagy and reduced intra-macrophage survival of M. tuberculosis.”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [80]
In the citing paper
“The effect of gefitinib could be traced back to blockade of EGFR mediated p38-MAPK activation, a known inhibitory pathway of autophagy (80).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [80]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
CellProfiler: image analysis software for identifying and quantifying cell phenotypes
Carpenter, A. E., Jones, T. R., Lamprecht, M. R., Clarke, C., Kang, I. H., Friman, O., Guertin, D. A., Chang, J. H., Lindquist, R. A., Moffat, J., et al. (2006) · Genome biology · doi:10.1186/gb-2006-7-10-r100 · Cited by 5,212
Self-citationTuberculosis Associated with Infliximab, a Tumor Necrosis Factor α–Neutralizing Agent
Keane, J., Gershon, S. K., Wise, R. P., Mirabile‐Levens, E., Kasznica, J. M., Schwieterman, W. D., Siegel, J. N., & Braun, M. M. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa011110 · Cited by 3,683
Mechanism of activation of protein kinase B by insulin and IGF‐1.
Alessi, D. R., Andjelković, M., Caudwell, B., Cron, P. D., MORRICE, N. A., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,014
Peyron, P., Vaubourgeix, J., Poquet, Y., Levillain, F., Botanch, C., Bardou, F., Daffé, M., Emile, J.-F., Marchou, B., Cardona, P.-J., et al. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000204 · Cited by 751
Gardam, M. A., Keystone, E. C., Menzies, R., Manners, S., Skamene, E., Long, R., & Vinh, D. C. (2003) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(03)00545-0 · Cited by 742
Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis
Pethe, K., Bifani, P. J., Jang, J., Kang, S., Park, S., Ahn, S., Jiřiček, J., Jung, J., Jeon, H. K., Cechetto, J. D., et al. (2013) · Nature Medicine · doi:10.1038/nm.3262 · Cited by 601
Roca, F. J., & Ramakrishnan, L. (2013) · Cell · doi:10.1016/j.cell.2013.03.022 · Cited by 592
Host Genotype-Specific Therapies Can Optimize the Inflammatory Response to Mycobacterial Infections
Tobin, D. M., Roca, F. J., Oh, S. F., McFarland, R., Vickery, T. W., Ray, J. P., Ko, D. C., Zou, Y., Bang, N. D., Chau, T. T. H., et al. (2012) · Cell · doi:10.1016/j.cell.2011.12.023 · Cited by 583
Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis
Lee, M., Lee, J., Carroll, M. W., Choi, H., Min, S., Song, T., Via, L. E., Goldfeder, L. C., Kang, E., Jin, B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1201964 · Cited by 557
Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism
Adams, K. N., Takaki, K. K., Connolly, L. E., Wiedenhoft, H., Winglee, K., Humbert, O., Edelstein, P. H., Cosma, C. L., & Ramakrishnan, L. (2011) · Cell · doi:10.1016/j.cell.2011.02.022 · Cited by 522
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–251 of 251
Antituberculosis agents: Beyond medicinal chemistry rules
Pieroni, M. (2019) · Annual reports in medicinal chemistry · doi:10.1016/bs.armc.2019.06.001 · Cited by 6
Xiao, Y., Zhang, T., Li, Y., Liu, C., Yang, S.-J., Zeng, L., Huang, S., Deng, X.-Y., & Peng, L. (2021) · Microbial Drug Resistance · doi:10.1089/mdr.2020.0511 · Cited by 6
Genetics-directed drug discovery for combating Mycobacterium tuberculosis infection
Quan, Y., Xiong, L., Chen, J., & Zhang, H. (2016) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2016.1157037 · Cited by 5
Autophagy as a Target for Host-Directed Therapy Against Tuberculosis
Verma, S., Sharma, R. D., & Kumar, D. (2020) · Springer eBooks · doi:10.1007/978-3-030-56905-1_6 · Cited by 4
Armesilla-Diaz, A., Arenaz-Callao, M. P., Ashby, C. A., Blanco, D., D’Oria, E., Garuti, H., Gómez, V., del Río, R. G., Martínez-Hoyos, M., Meiler, E., et al. (2025) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01613-24 · Cited by 4
Manipulation of autophagy for host-directed tuberculosis therapy
Gina, P., Davids, M., & Dheda, K. U. J. (2019) · African Journal of Thoracic and Critical Care Medicine · doi:10.7196/sarj.2019.v25i2.014 · Cited by 4
Dombach, J. L., Christensen, G. L., Allgood, S. C., Quintana, J. L. J., & Detweiler, C. S. (2024) · mSphere · doi:10.1128/msphere.00772-23 · Cited by 6
Sable, S. B., Li, W., Kline, A., Govindaraj, S., Velu, V., & Posey, J. E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.27.672670 · Cited by 3
When to Die Is the Question: Need and Manipulation of Cell Death by Mycobacterium
Mittal, E., Deore, S., Kumar, M., & Krishnasastry, M. V. (2020) · Current Molecular Biology Reports · doi:10.1007/s40610-020-00137-w · Cited by 3
Sudasinghe, T. D., Banco, M. T., & Ronning, D. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-01526-6 · Cited by 3
Wumaier, R., Zhang, K., Zhou, J., Wen, Z., Chen, Z., Luo, G., Wang, H., Qin, J., Du, B., Ren, H., et al. (2025) · Microorganisms · doi:10.3390/microorganisms13010110 · Cited by 2
Gupta, A., Mehta, S. B., Abhimanyu, A., Rosa, B. A., Martin, J. C., Ahmed, M., Thirunavukkarasu, S., Fatma, F., Amarasinghe, G. K., Mitreva, M., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.185582 · Cited by 2
Innate Immune Responses to Tuberculosis
Schorey, J. S., & Schlesinger, L. S. (2017) · ASM Press eBooks · doi:10.1128/9781555819569.ch1 · Cited by 2
Host-Directed Omics Approaches to Tackle Antimicrobial Resistance
Rastogi, S., & Chandra, P. (2024) · Springer eBooks · doi:10.1007/978-3-031-65986-7_10 · Cited by 2
Cell-Based Assays in Natural Product-Based Drug Discovery
Mukne, A., Momin, M., Betkar, P., Rane, T., & Valecha, S. (2021) · Springer eBooks · doi:10.1007/978-981-15-8127-4_11 · Cited by 2
Immunological implications of epidermal growth factor receptor signaling in persistent infections
Mukherjee, T., & Balaji, K. N. (2019) · IUBMB Life · doi:10.1002/iub.2115 · Cited by 2
Targeting Inhibitory Cells Such as Tregs and MDSCs in the Tuberculous Granuloma
Parveen, S., Murphy, J. R., & Bishai, W. R. (2020) · Springer eBooks · doi:10.1007/978-3-030-56905-1_11 · Cited by 2
Njikan, S., Ahmed, S., Manning, A. J., Awasthi, D., Ovechkina, Y., Chowdhury, S., Butts, A., & Parish, T. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.01161-22 · Cited by 2
Newer Patents in Antimycobacterial Therapy
Shahid, S. (2015) · Pharmaceutical Patent Analyst · doi:10.4155/ppa.15.9 · Cited by 2
Simwela, N. V., Johnston, L., Bitar, P. P., Jaecklein, E., Altier, C., Sassetti, C. M., & Russell, D. G. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.06.592714 · Cited by 2
Gunnarsson, C., McGinn, R. A., Hochfelder, J. B., & Bryson, B. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.17.683041 · Cited by 2
Host-Directed Therapies for TuberculosisPreprint
Oehlers, S. H., Agarwal, S., & Singhal, A. (2026) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041823 · Cited by 3
Vijayalakshmi, P., Alfaiz, F. A., Vijayakumar, R., Desai, D., & Selvaraj, C. (2025) · Microbial Pathogenesis · doi:10.1016/j.micpath.2025.108173 · Cited by 1
Patel, S., Behera, S., Naik, L., Das, M., Nayak, D. K., Dandsena, P. K., Quaderi, M. A., Mishra, A., Singh, R., Das, S., et al. (2026) · Microbial Pathogenesis · doi:10.1016/j.micpath.2026.108297 · Cited by 1
Parapini, S., D’Alessandro, S., Travaglione, S., Paone, S., Cuevas, I. M. M., Dipol, T., Zongo, D. W. R., Vazquez, A. M. F., Morsilli, O., Fabbri, A., et al. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.118690 · Cited by 1
Xing, X., Liu, H., Pang, Y., & Li, S. (2026) · Microbial Pathogenesis · doi:10.1016/j.micpath.2026.108850 · Cited by 1
Gamarra, M., & Zurek, E. E. (2017) · Iberian Conference on Information Systems and Technologies (CISTI) · doi:10.23919/cisti.2017.7975726 · Cited by 1
Bernard, L. (2020) · theses.fr (ABES) · doi:10.70675/589a776dz18d9z4813z9d6fzd73632aa4df7 · Cited by 1
Discovery of a Small Molecule That Inhibits D-Alanylation of Teichoic Acids in Staphylococcus Aureus
Pasquina, L. W. (2015) · Digital Access to Scholarship at Harvard (DASH) (Harvard University)
Fourie, P. B., & Hafner, R. (2016) · Wiley eBooks · doi:10.1002/9781118943182.ch20
Expression pattern of the autophagy related proteins Beclin1 and LC3B in tuberculous wound tissues
Zhou, K., Su, Y., & Jia, C. (2021) · European Journal of Inflammation · doi:10.1177/20587392211024808
Jung, W. (2021) · arXiv (Cornell University) · doi:10.48550/arxiv.2108.01625
The role of Lymphoblastic leukemia 1 (Lyl1) in Mycobacterium tuberculosis (Mtb) infection
Jones, S.-S. (2021) · Open University of Cape Town (University of Cape Town)
Host-Microbial Relationship: Immune Response to Microbial Infections with or without Medication
Pappoe, F., & Nuvor, S. V. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.97814
Kalsum, S., Andersson, B., Das, J., Schön, T., & Lerm, M. (2021) · Research Square · doi:10.21203/rs.3.rs-133359/v1
(2021) · Elsevier eBooks · doi:10.1016/b978-0-12-816983-4.00003-1
Kalsum, S., Andersson, B., Das, J., Schön, T., & Lerm, M. (2021) · Figshare · doi:10.6084/m9.figshare.14738829
Asamoto, C. K., Ewing, C. A., Meyer, C. T., Allgood, S. C., Eldridge, M. J. G., Evans, D., Nagy, T. A., Christensen, G. L., Crooks, A. L., Jiang, D., et al. (2025) · Microbiology Spectrum · doi:10.1128/spectrum.03217-25
Autophagy is essential for anti-Wolbachia drug efficacy in Brugia malayi and insect cells
Yousef, A., Masters, E. K. G., Wu, Y., Hong, W. D., O’Neill, P. M., Turner, J. D., Ward, S. A., & Taylor, M. J. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1771755
Modulation de l'autophagie des macrophages : rôle des lipides de l'enveloppe
Bah, A. (2017) · theses.fr (ABES) · doi:10.70675/0170380fz0af5z4c02za7aezd5ac5153ffd8
PLK2 facilitates Mycobacterium tuberculosis clearance via p38 MAPK–mediated ROS production
Liu, Y., Chen, L., Wang, L., Yang, H., Pang, Y., Li, Q., Guo, Y., & Lu, J. (2026) · Clinical Immunology · doi:10.1016/j.clim.2026.110705
Immunomodulators as Therapy for Mycobacteria
Agrawal, F., & Maurya, A. K. (2026) · Springer eBooks · doi:10.1007/978-981-92-0256-0_15
Xu, Y., Fang, M., Jin, Z., Li, Y., Ma, F., Lu, Z., Wang, H., Li, P., & Zhang, L. (2026) · Journal of Future Foods · doi:10.1016/j.jfutfo.2026.05.020
SH3PXD2B is the critical host factor promoting the entry of mycobacteria
Liu, D., Zhang, T., Sheng, Y., Xu, Z., Zheng, C., Chen, Y., Guo, A., Jiao, X., & Chen, X. (2026) · Applied and Environmental Microbiology · doi:10.1128/aem.00675-26
Advancing Therapies for Mycobacterial Diseases: From Small Molecules to Host‐Directed Strategies
Silva, T., Aiello, A., Alonzi, T., Carvalho, M. A., Finger, V., Goletti, D., Hoffner, S., Kherabi, Y., Korábečný, J., Kulczyńska, J., et al. (2026) · Medicinal Research Reviews · doi:10.1002/med.70096
Saha, S., Павловна, С. Н., Gizinger, O., Голікова, Н., Мухтаровна, А. А., Grushko, M., & Molchanova, M. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1916875
Chen, T., Ge, L., Zhang, D., Zhang, Y., Zhang, H., & Wang, Y. (2026) · Genes · doi:10.3390/genes17101198
Pinnelli, V. B. K., THANGACHI, S. B., Jayashankar, C. A., Kandi, V., Manish, G. R., Sam, K. T., Raju, P. K. R. B., Sucharitha, A. S., Barman, A., Sainath, G., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1994202
Advances in host-directed therapies for tuberculosis
Shaku, M. T., & Bishai, W. R. (2026) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2026.2750203
Kou, Z., Han, J., Xue, Y., Fu, Y., Yi, Z., & Li, M. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117598
Metadata
- Authors
- Stanley, S. A., Barczak, A. K., Silvis, M. R., Luo, S. S., Sogi, K., Vokes, M., Bray, M.-A., Carpenter, A. E., Moore, C. B., Siddiqi, N., Rubin, E. J., & Hung, D. T.
- Affiliations
- Broad Institute (US)
- University of California, Berkeley (US)
- Harvard University (US)
- Corresponding author
- Hung, Deborah T.
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-02-20
- Volume
- 10
- Issue
- 2
- Pages
- e1003946
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3930586
- OpenAlex
- W2009324985
- Cited by
- 251
- References
- 63
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 14 · 2023: 8 · 2022: 19 · 2021: 35 · 2020: 24 · 2019: 18 · 2018: 19 · 2017: 21 · 2016: 32 · 2015: 30 · 2014: 6
- FWCI
- 20.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Helen Hay Whitney Foundation
- Broad Institute
- National Institutes of Health (NIH-R01)
- National Institute of General Medical Sciences (R01GM089652)
- National Institute of Allergy and Infectious Diseases (K08AI080944, T32AI007061)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Mycobacterium tuberculosis, host-pathogen interaction, macrophages, intracellular bacterial growth, autophagy, TNF-alpha secretion, gefitinib, EGFR signaling, p38 MAPK signaling, fluoxetine, tuberculosis drug discovery, ion channel inhibitors
- MeSH terms
- Animals, Antitubercular Agents, Disease Models, Animal, Macrophages, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mycobacterium tuberculosis, Tuberculosis, Signal Transduction, Mice, Host-Pathogen Interactions, High-Throughput Screening Assays
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
