Biapenem reduces sepsis mortality via barrier protective pathways against HMGB1-mediated septic responses.

Abstract

As a late mediator of sepsis, the role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies for sepsis. For repositioning of previously FDA-approved drugs to develop new therapies for human diseases, screening of chemical compound libraries, biological active, is an efficient method. Our study illustrates an example of drug repositioning of Biapenem (BIPM), a carbapenem antibiotic, for the modulation of HMGB1-induced septic responses. We tested our hypothesis that BIPM inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model, antiseptic activity of BIPM was investigated from suppression of vascular permeability, pro-inflammatory proteins, and markers for tissue injury. BIPM significantly suppressed release of HMGB1 both in LPS-activated HUVECs (upto 60%) and the CLP-induced sepsis mouse model (upto 54%). BIPM inhibited hyperpermeability (upto 59%) and reduced HMGB1-mediated vascular disruptions (upto 62%), mortality (upto 50%), and also tissue injury including lung, liver, and kidney in mice. Reduction of HMGB1 release and septic mortality by BIPM (in vitro, from 5 to 15μM for 6h; in vivo, from 0.37 to 1.1mg/kg, 24h) indicate a possibility of successful repositioning of BIPM for the treatment of sepsis.