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.

Outer Membrane Vesicles Derived From Escherichia coli Regulate Neutrophil Migration by Induction of Endothelial IL-8

“…From the cell culture supernatants, we isolated E. coli OMVs by the combination of ultrafiltration and ultracentrifugation as previously reported ( Park et al, 2010 ; Kim et al, 2018 ). When we characterized isolated E. coli OMVs with transmission electron microscopy and dynamic light scattering, E. coli OMVs had spherical bilayered vesicular structures with diameters ranging from 20 to 100 nm ( Supplementary Figures 1A,B ).…”

Extracellular Vesicle–Mimetic Ghost Nanovesicles for Delivering Anti‐Inflammatory Drugs to Mitigate Gram‐Negative Bacterial Outer Membrane Vesicle–Induced Systemic Inflammatory Response Syndrome

“…We have previously shown that E. coli OMVs mediate SIRS upon intraperitoneal administration to mice, and repositioned drugs to mitigate E. coli OMV–induced SIRS . In addition, we developed extrusion‐based extracellular vesicle–mimetic NVs which deliver chemotherapeutics to the tumor tissues .…”

Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions

“…Salbutamol ( Fig. 13 , 93 ) is used for bronchial asthma, but is found also to affect cancer by activating the β 2 adrenoreceptor 110 . Raloxifene ( Fig.…”

“…Accordingly, many FDA-approved drugs or experimental drugs used for treating other diseases can be reused for exploring their potential antitumor effects 142 . Repurposed drugs can be further investigated according to their off-target effects, which might be inversely related to their therapeutic target in cancer 110 . Based on the retrospective clinical data, prior knowledge of the side effects of old drugs may have a huge therapeutic potential on different types of human cancers.…”