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Because of its potential as a bioterrorism agent, there is a need for new therapeutic agents. We therefore developed a whole-animal<jats:named-content content-type=\"genus-species\">Caenorhabditis elegans<\/jats:named-content>-<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>pathosystem for high-throughput screening to identify and characterize potential therapeutic compounds. We found that the<jats:named-content content-type=\"genus-species\">C. elegans<\/jats:named-content>p38 mitogen-activate protein (MAP) kinase cascade is involved in the immune response to<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>, and we developed a robust<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>-mediated<jats:named-content content-type=\"genus-species\">C. elegans<\/jats:named-content>killing assay with a Z\u2032 factor consistently of &gt;0.5, which was then utilized to screen a library of FDA-approved compounds that included 1,760 small molecules. In addition to clinically used antibiotics, five FDA-approved drugs were also identified as potential hits, including the anti-inflammatory drug diflunisal that showed anti-<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>activity<jats:italic>in vitro<\/jats:italic>. Moreover, the nonsteroidal anti-inflammatory drug (NSAID) diflunisal, at 4\u00d7 MIC, blocked the replication of an<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>live vaccine strain (LVS) in primary human macrophages and nonphagocytic cells. Diflunisal was nontoxic to human erythrocytes and HepG2 human liver cells at concentrations of \u226532 \u03bcg\/ml. Finally, diflunisal exhibited synergetic activity with the antibiotic ciprofloxacin in both a checkerboard assay and a macrophage infection assay. In conclusion, the liquid<jats:named-content content-type=\"genus-species\">C. elegans<\/jats:named-content>-<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>LVS assay described here allows screening for anti-<jats:named-content content-type=\"genus-species\">F. tularensis<\/jats:named-content>compounds and suggests that diflunisal could potentially be repurposed for the management of tularemia.<\/jats:p>","DOI":"10.1128\/aac.00310-17","type":"journal-article","created":{"date-parts":[[2017,6,27]],"date-time":"2017-06-27T00:30:31Z","timestamp":1498523431000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds"],"prefix":"10.1128","volume":"61","author":[{"given":"Elamparithi","family":"Jayamani","sequence":"first","affiliation":[{"name":"Division of 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