Influence of Lipopolysaccharide-Interacting Peptides Fusion with Endolysin LysECD7 and Fatty Acid Derivatization on the Efficacy againstInfection In Vitro and In Vivo.

Abstract

has developed multiple drug resistances, posing a significant threat to antibiotic efficacy. LysECD7, an endolysin derived from phages, could be a promising therapeutic agent against multi-drug resistance. In this study, in order to further enhance the antibacterial efficiency of the engineered LysECD7, a few lipopolysaccharide-interacting peptides (Li5, MSI594 and Li5-MSI) were genetically fused with LysECD7. Based on in vitro antibacterial activity, the fusion protein Lys-Li5-MSI was selected for further modifications aimed at extending its half-life. A cysteine residue was introduced into Lys-Li5-MSI through mutation (Lys-Li5-MSI), followed by conjugation with a C16 fatty acid chain via a protonation substitution reaction(V12C-C16). The pharmacokinetic profile of V12C-C16 exhibited a more favorable characteristic in comparison to Lys-Li5-MSI, thereby resulting in enhanced therapeutic efficacy against lethalinfection in mice. The study provides valuable insights for the development of novel endolysin therapeutics and proposes an alternative therapeutic strategy for combatinginfections.