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

Abstract

Sepsis is characterized by systemic inflammatory response syndrome (SIRS) accompanied with infection. Gram-negative bacteria can evoke sepsis by activating the host immune system, such as the release of IL-6 and TNF-α, through their virulence factors. Outer membrane vesicles (OMVs), nanosized bilayered proteolipids derived from Gram-negative bacteria, harbor various virulence factors and are shown to induce SIRS. Here, drugs are repositioned to alleviate SIRS caused by Gram-negative bacterial OMVs. Using novel OMV-based drug screening systems, a total of 178 commercially available drugs are primarily screened, and a total of 18 repositioned drug candidates are found to effectively block IL-6 and TNF-α production from OMV-stimulated macrophages. After excluding the compounds which are previously known to intervene sepsis or which show cytotoxicity to macrophages, the compounds which show dose-dependency in inhibiting the release of IL-6 and TNF-α by the OMV-stimulated macrophages in vitro and which reduce OMV-induced SIRS in vivo are selected. Salbutamol, a β2 adrenergic receptor agonist, is selected as a novel candidate to alleviate OMV-induced SIRS. This study sheds light on using Gram-negative bacterial OMVs in exploring novel candidate compounds to alleviate inflammatory diseases including sepsis.

Keywords: drug repositioning; extracellular vesicles; outer membrane vesicles; sepsis; systemic inflammatory response syndrome.