Limosilactobacillus reuteri-derived tripeptide SKL exerts antibacterial activity against systemic and wound infections via dual membrane-killing and anti-virulence mechanisms
摘要
The escalating crisis of antimicrobial resistance (AMR) necessitates innovative antimicrobial strategies beyond conventional antibiotics. Although the beneficial effects of probiotics are well recognized, the specific molecular effectors responsible for their systemic protective functions remain largely unexplored. Here, we screened the piglet gut microbiota and identified Limosilactobacillus reuteri P190 as a strain with potent, broad-spectrum activity against diverse bacterial pathogens and robust protection against lethal systemic Salmonella infection in vivo. Mechanistic investigations revealed that this protective effect is attributed to a novel tripeptide, Ser-Lys-Leu (SKL). SKL exerts a unique dual mode of action: it rapidly disrupts bacterial cell membranes at inhibitory concentrations, while simultaneously attenuating virulence by targeting the QseC quorum-sensing system even at sub-inhibitory concentrations. Notably, through tandem-repeat engineering, we developed a highly potent variant, (SKL)4, which dramatically enhances direct antimicrobial efficacy while retaining low hemolysis and cytotoxicity. Both SKL and (SKL)4 protect mice from lethal systemic Salmonella challenges independent of host immunity, demonstrating their direct, autonomous therapeutic power. Furthermore, topical applications of these peptides successfully cleared methicillin-resistant Staphylococcus aureus wound infections and accelerated healing, with efficacy comparable to that of mupirocin. Collectively, our findings identify SKL as a promising probiotic-derived lead antimicrobial peptide with dual membrane-disrupting and anti-virulence capabilities, offering a compelling strategy to combat multidrug-resistant pathogens.
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