PDF(Pubmed)
Abstract：
Acinetobacter baumannii 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 A. baumannii. 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-MSIV12C), 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 lethal A. baumannii infection in mice. The study provides valuable insights for the development of novel endolysin therapeutics and proposes an alternative therapeutic strategy for combating A. baumannii infections.
摘要：
鲍曼不动杆菌已产生多种耐药性,对抗生素功效构成重大威胁。LysECD7，一种来自噬菌体的内溶素，可能是一种有前途的抗多药耐药鲍曼不动杆菌的治疗剂。在这项研究中,为了进一步增强工程LysECD7的抗菌效率,将一些脂多糖相互作用肽(Li5、MSI594和Li5-MSI)与LysECD7基因融合。基于体外抗菌活性，选择融合蛋白Lys-Li5-MSI进行旨在延长其半衰期的进一步修饰。通过突变(Lys-Li5-MSIV12C)将半胱氨酸残基引入Lys-Li5-MSI,然后通过质子化取代反应与C16脂肪酸链缀合(V12C-C16)。与Lys-Li5-MSI相比，V12C-C16的药代动力学特征表现出更有利的特征，从而在小鼠中导致增强的针对致死鲍曼不动杆菌感染的治疗功效。该研究为新型内溶素疗法的开发提供了有价值的见解，并提出了对抗鲍曼不动杆菌感染的替代治疗策略。
