{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:13:33Z","timestamp":1770743613770,"version":"3.49.0"},"reference-count":57,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United States Army Medical Research and Development Command, Military Infectious Disease Research Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>In the military, combat wound infections can progress rapidly to life-threatening sepsis. The discovery of effective small-molecule drugs to prevent and\/or treat sepsis is a priority. To identify potential sepsis drug candidates, we used an optimized larval zebrafish model of endotoxicity\/sepsis to screen commercial libraries of drugs approved by the U.S. Food and Drug Administration (FDA) and other active pharmaceutical ingredients (APIs) known to affect pathways implicated in the initiation and progression of sepsis in humans (i.e., inflammation, mitochondrial dysfunction, coagulation, and apoptosis). We induced endotoxicity in 3- and 5-day post fertilization larval zebrafish (characterized by mortality and tail fin edema (vascular leakage)) by immersion exposure to 60 \u00b5g\/mL Pseudomonas aeruginosa lipopolysaccharide (LPS) for 24 h, then screened for the rescue potential of 644 selected drugs at 10 \u00b5M through simultaneous exposure to LPS. After LPS exposure, we used a neurobehavioral assay (light-dark test) to further evaluate rescue from endotoxicity and to determine possible off-target drug side effects. We identified 29 drugs with &gt; 60% rescue of tail edema and mortality. Three drugs (Ketanserin, Tegaserod, and Brexpiprazole) produced 100% rescue and did not differ from the controls in the light-dark test, suggesting a lack of off-target neurobehavioral effects. Further testing of these three drugs at a nearly 100% lethal concentration of Klebsiella pneumoniae LPS (45 \u00b5g\/mL) showed 100% rescue from mortality and 88\u2013100% mitigation against tail edema. The success of the three identified drugs in a zebrafish endotoxicity\/sepsis model warrants further evaluation in mammalian sepsis models.<\/jats:p>","DOI":"10.3390\/life14121689","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T08:40:25Z","timestamp":1734684025000},"page":"1689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of Potential Sepsis Therapeutic Drugs Using a Zebrafish Rapid Screening Approach"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6301-1028","authenticated-orcid":false,"given":"Mark","family":"Widder","sequence":"first","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chance","family":"Carbaugh","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"},{"name":"General Dynamics Information Technology, Falls Church, VA 22042, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"van der Schalie","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"},{"name":"Culmen International, LLC, Alexandria, VA 22314, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Ronald","family":"Miller","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"},{"name":"General Dynamics Information Technology, Falls Church, VA 22042, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Brennan","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"},{"name":"General Dynamics Information Technology, Falls Church, VA 22042, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Moore","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8745-2805","authenticated-orcid":false,"given":"Robert","family":"Campbell","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5843-5363","authenticated-orcid":false,"given":"Kevin","family":"Akers","sequence":"additional","affiliation":[{"name":"Audie L. Murphy VA Medical Center, San Antonio, TX 78229, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roseanne","family":"Ressner","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Martin","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6000-2599","authenticated-orcid":false,"given":"Michael","family":"Madejczyk","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8610-6073","authenticated-orcid":false,"given":"Blair","family":"Dancy","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Lee","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Lanteri","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1089\/sur.2017.240","article-title":"Early infections complicating the care of combat casualties from Iraq and Afghanistan","volume":"19","author":"Weintrob","year":"2018","journal-title":"Surg. 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