Identification of Potential Sepsis Therapeutic Drugs Using a Zebrafish Rapid Screening Approach

Area of Science:

• Pharmacology
• Toxicology
• Infectious Diseases

Background:

• Sepsis, a life-threatening condition often stemming from combat wound infections, poses a significant challenge in military medicine.
• Developing effective small-molecule drugs to prevent or treat sepsis is a critical medical priority.

Purpose of the Study:

• To screen U.S. Food and Drug Administration (FDA)-approved drugs and active pharmaceutical ingredients (APIs) for sepsis treatment potential.
• To identify novel drug candidates for sepsis using a larval zebrafish model of endotoxicity.

Main Methods:

• An optimized larval zebrafish model was used to induce endotoxicity via lipopolysaccharide (LPS) exposure.
• 644 FDA-approved drugs and APIs were screened for their ability to rescue zebrafish from LPS-induced mortality and vascular leakage (edema).
• A neurobehavioral assay (light-dark test) was employed to assess drug efficacy and identify potential off-target effects.

Main Results:

• 29 drugs demonstrated over 60% rescue from endotoxicity.
• Ketanserin, Tegaserod, and Brexpiprazole achieved 100% rescue from mortality and edema without neurobehavioral side effects.
• These three drugs also showed high efficacy against a lethal concentration of *Klebsiella pneumoniae* LPS.

Conclusions:

• Ketanserin, Tegaserod, and Brexpiprazole show significant promise as potential sepsis therapeutics.
• The identified drugs warrant further investigation in mammalian sepsis models for clinical translation.
• The larval zebrafish model is a viable platform for rapid screening of sepsis drug candidates.