Synergistic Antibacteria and Anti-Inflammation with Reversible Redox Selenium-Functionalized Polypeptides for...

Area of Science:

• Biochemistry
• Materials Science
• Immunology

Background:

• Gram-negative sepsis is a major cause of ICU mortality, driven by inflammation and antimicrobial resistance.
• Antibiotic treatment can worsen sepsis by releasing lipopolysaccharide (LPS), triggering a harmful inflammatory response.
• There is a critical need for therapies that simultaneously address bacterial infection and host inflammation.

Purpose of the Study:

• To develop novel selenium-functionalized polypeptides with combined antibacterial and anti-inflammatory properties.
• To investigate the mechanism of action of these peptides against Gram-negative bacteria and sepsis-induced inflammation.
• To evaluate the therapeutic efficacy of the optimal peptide in preclinical sepsis models.

Main Methods:

• Synthesis and characterization of selenium-functionalized polypeptides.
• Assessment of antibacterial activity against Gram-negative bacteria (e.g., E. coli, P. aeruginosa).
• In vitro and in vivo evaluation of anti-inflammatory effects, including LPS neutralization and TLR4 signaling inhibition.
• Testing in murine models of cecal ligation/puncture (CLP) sepsis and E. coli peritonitis.

Main Results:

• The peptide PSe50-CF demonstrated broad-spectrum activity against Gram-negative bacteria, including ESCAPE pathogens.
• PSe50-CF targets LPS and phospholipids, disrupting bacterial membranes and inhibiting LPS biosynthesis.
• The peptide effectively neutralized LPS, suppressed TLR4 signaling, and reduced proinflammatory cytokines in vitro and in vivo.
• Significant therapeutic benefits were observed in CLP and E. coli peritonitis sepsis models.

Conclusions:

• Selenium-functionalized polypeptides, like PSe50-CF, present a dual-action therapeutic strategy for Gram-negative sepsis.
• This approach effectively combats bacterial infection and mitigates detrimental host inflammation.
• These findings establish a promising new direction for next-generation antimicrobial drug design against sepsis.