Identification of potential sepsis therapeutic drugs using a zebrafish rapid screening approach
Abstract
Abstract In the military, combat wound infections can progress rapidly to life-threatening sepsis. 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 (Philip et al., 2017) to screen commercial libraries of U.S. Food and Drug Administration (FDA)- approved drugs and other active pharmaceutical ingredients (API) 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 Pseudomonas aeruginosa 60 μg/mL lipopolysaccharide (LPS) for 24 hours, then screened for the rescue potential of 644 selected drugs simultaneously with LPS at 10 μM. 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 > 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…
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Evidence Hub reads this as a preprint, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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