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Abstract: 

Gram-negative sepsis, a leading cause of intensive care units mortality, is exacerbated by dysregulated host inflammation and escalating antimicrobial resistance. The release of lipopolysaccharide (LPS) following antibiotic treatment and the resulting proinflammatory cascade necessitate simultaneous application of effective inflammation management. Herein, we developed a series of selenium-functionalized polypeptides with the reversible redox properties of selenium and positive charge units, having negative antibacteria and anti-inflammation synchronously. The optimal peptide, PSe50-CF, can effectively kill many Gram-negative bacteria, including E. coli, P. aeruginosa and A. baumannii belonging to ESCAPE family. PSe50-CF disrupts outer membrane integrity and inhibits LPS biosynthesis via dual targeting of LPS and phospholipids and further downregulating critical genes for lipid A biosynthesis and the BamA component of the β-barrel assembly machinery (BAM complex). Crucially, leveraging selenium's reversible redox and immune regulation properties, PSe50-CF exhibited potent anti-inflammatory effects both in vitro and in vivo by neutralizing LPS and suppressing Toll-like receptor 4 (TLR4) signaling, thereby blocking proinflammatory cytokine. This dual-action mechanism translates to superior therapeutic efficacy in murine models of cecal ligation/puncture (CLP) sepsis and E. coli-induced peritonitis. Together, these findings position selenium-functionalized polypeptides as a highly promising therapeutic strategy for Gram-negative sepsis therapy and a paradigm for next-generation antimicrobial design.