A stable cyclized antimicrobial peptide derived from LL-37 with host immunomodulatory effects and activity against uropathogens

The increasing antibiotic resistance among uropathogenic bacteria warrants alternative therapeutic strategies. We demonstrate the potential of the synthetic peptide CD4-PP, designed by dimerization and backbone cyclization of the shortest antimicrobial region of human cathelicidin, LL-37. CD4-PP is active against clinical and type strains of common uropathogens Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa at concentrations substantially below cellular cytotoxic levels and induced membrane deformation and leakage in E. coli and P. aeruginosa. Furthermore, CD4-PP treatment prevented the formation of new biofilm and dissolved mature biofilm created by E. coli and P. aeruginosa and targeted curli amyloid in E. coli biofilms. In addition, CD4-PP also induced production of LL-37 by uroepithelial cells and increased the expression of tight junction proteins claudin-14 and occludin. During uroepithelial cell infection, CD4-PP significantly reduced uropathogen survival when treatment was given at the start of infection. Low micromolar of CD4-PP treatment initiated after 2 h was successful with all tested species, except P. aeruginosa where CD4-PP was unable to reduce survival, which could be attributed by early biofilm formation. Finally, we demonstrated that urinary catheter pieces coated with saline fluid supplemented with CD4-PP reduced the attachment of E. coli, giving it a potential clinical application.

Automated summary

The synthetic peptide CD4-PP, designed by dimerization and backbone cyclization of the antimicrobial region of human cathelicidin, LL-37, shows potential as an alternative therapy for uropathogenic bacteria. It is active against common uropathogens at low concentrations and can prevent biofilm formation, dissolve mature biofilms, and induce production of antimicrobial peptide and tight junction proteins by uroepithelial cells. It also reduces uropathogen survival during cell infection. Coating urinary catheter pieces with CD4-PP can reduce the attachment of E. coli.