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Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Yersinia pestis<\/jats:named-content>CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Y. pestis<\/jats:named-content>-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in<jats:italic>in vitro<\/jats:italic>screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if<jats:italic>in vitro<\/jats:italic>efficacy could be translated<jats:italic>in vivo<\/jats:italic>. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Y. pestis<\/jats:named-content>and having no modulating effect on crucial<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Y. pestis<\/jats:named-content>virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from<jats:italic>in vitro<\/jats:italic>screens, the therapeutic potential of TFP, the most efficacious drug<jats:italic>in vivo<\/jats:italic>, was evaluated in murine models of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Salmonella enterica<\/jats:named-content>serovar Typhimurium and<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Clostridium difficile<\/jats:named-content>infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.<\/jats:p>","DOI":"10.1128\/aac.00326-16","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T03:39:01Z","timestamp":1460432341000},"page":"3717-3729","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":53,"title":["New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria"],"prefix":"10.1128","volume":"60","author":[{"given":"Jourdan A.","family":"Andersson","sequence":"first","affiliation":[{"name":"Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Fitts","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Kirtley","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duraisamy","family":"Ponnusamy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex G.","family":"Peniche","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Dann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, UTMB, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir L.","family":"Motin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA"},{"name":"Department of Pathology, UTMB, Galveston, Texas, USA"},{"name":"WHO Collaborating Center for Vaccine Development, UTMB, Galveston, Texas, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadhana","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason A.","family":"Rosenzweig","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas Southern University, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Sha","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok K.","family":"Chopra","sequence":"additional","affiliation":[{"name":"Institute for Translational Sciences, University of Texas Medical Branch (UTMB), Galveston, Texas, USA"},{"name":"Department of Microbiology and Immunology, UTMB, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, UTMB, Galveston, Texas, USA"},{"name":"WHO Collaborating Center for Vaccine Development, UTMB, Galveston, Texas, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, UTMB, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Antibiotic resistant threats in the United States, 2013, p 1\u2013114","author":"CDC","year":"2013","unstructured":"CDC. 2013. 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