Drug Repositioning to Alleviate Systemic Inflammatory Response Syndrome Caused by Gram-Negative Bacterial Outer...

Area of Science:

• Microbiology and Immunology
• Pharmacology
• Biotechnology

Background:

• Sepsis, a life-threatening condition, involves systemic inflammatory response syndrome (SIRS) triggered by infection.
• Gram-negative bacteria, through virulence factors like outer membrane vesicles (OMVs), can induce SIRS by activating immune responses, including the release of IL-6 and TNF-α.
• OMVs are nanoscale bacterial components that harbor virulence factors and can initiate SIRS.

Purpose of the Study:

• To identify and reposition existing drugs for alleviating SIRS caused by Gram-negative bacterial OMVs.
• To explore novel therapeutic candidates for sepsis and related inflammatory conditions.

Main Methods:

• A high-throughput drug screening system using OMV-stimulated macrophages was developed.
• 178 commercially available drugs were screened for their ability to inhibit IL-6 and TNF-α production.
• Selected drug candidates were further evaluated for dose-dependent inhibition in vitro and efficacy in reducing OMV-induced SIRS in vivo, while excluding cytotoxic or pre-existing sepsis-related compounds.

Main Results:

• 18 drug candidates were initially identified for blocking IL-6 and TNF-α production from OMV-stimulated macrophages.
• After rigorous exclusion criteria, Salbutamol, a β2 adrenergic receptor agonist, was selected.
• Salbutamol demonstrated dose-dependent inhibition of IL-6 and TNF-α release in vitro and reduced OMV-induced SIRS in vivo.

Conclusions:

• Gram-negative bacterial OMVs can serve as a valuable tool for discovering novel therapeutic compounds.
• Salbutamol emerges as a promising candidate for alleviating OMV-induced SIRS and potentially sepsis.
• This research opens new avenues for drug repositioning in the treatment of inflammatory diseases.