AUTHOR=Mohanty Soumitra , White John Kerr , Yin Yundi , Muhammad Taj , Demirel Isak , Strömstedt Adam A. , Gunasekera Sunithi , Ferraz Natalia , Göransson Ulf , Brauner Annelie 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1705805

DOI=10.3389/fimmu.2025.1705805

ISSN=1664-3224

ABSTRACT=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 Escherichia coli–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 E. coli as well as ESBL-producing and multi-drug resistant E. coli. 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 E. coli 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.