Synthetic antimicrobial peptide LD4-PP protects the host against E. coli-induced cell death

With antibiotic resistance being a major global concern, there is a huge need of new treatment options to fight bacterial infections. In this study, we highlight the antibacterial and host-protective roles of a novel synthetic antimicrobial peptide in uropathogenic <i>Escherichia coli</i>-infected uroepithelial cells. This peptide, designed from a fragment of human cathelicidin LL-37 and named LD4-PP, was found to be highly potent against clinical isolates of <i>E. coli</i> as well as ESBL-producing and multi-drug resistant <i>E. coli.</i> Additionally, LD4-PP inhibited the formation of new biofilm, damaging both the bacterial surface and the bacterial genome. LD4-PP also modulated the host cell lipid vacuole, caveolin-1, and Rho GTPase B affecting bacterial survival. Furthermore, LD4-PP exerts immunomodulatory effects by modulating free radical formation, expression of antioxidants, and inflammasome-mediated cell death. Pronounced uroepithelial cell death was observed after <i>E. coli</i> infection which was significantly inhibited by LD4-PP without affecting the cellular toxicity. Overall, the peptide LD4-PP is shown to be a strong candidate for future clinical applications, particularly to prevent and treat urinary tract infections.