• 作者： Jeonghyun Lim, Heejoon Myung, Daejin Lim & Miryoung Song
• 作者服務機構： 1.Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin, 17035, Republic of Korea 2.Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341, Republic of Korea 3.LyseNTech Co., Ltd., Seongnam-Si, 13486, Republic of Korea
• 中文摘要：
• 英文摘要：
  Background
  This study addresses the urgent need for infection control agents driven by the rise of drug-resistant pathogens such as Acinetobacter baumannii. Our primary aim was to develop and assess a novel endolysin, Tha-PA90, designed to combat these challenges.
  
  Methods
  Tha-PA90 incorporates an antimicrobial peptide (AMP) called thanatin at its N-terminus, enhancing bacterial outer membrane permeability and reducing host immune responses. PA90 was selected as the endolysin component. The antibacterial activity of the purified Tha-PA90 was evaluated using an in vitro colony-forming unit (CFU) reduction assay and a membrane permeability test. A549 cells were utilized to measure the penetration into the cytosol and the cytotoxicity of Tha-PA90. Finally, infection control was monitored in A. baumannii infected mice following the intraperitoneal administration of Tha-PA90.
  
  Results
  Tha-PA90 demonstrated remarkable in vitro efficacy, completely eradicating A. baumannii strains, even drug-resistant variants, at a low concentration of 0.5 μM. Notably, it outperformed thanatin, achieving only a < 3-log reduction at 4 μM. Tha-PA90 exhibited 2–3 times higher membrane permeability than a PA90 and thanatin mixture or PA90 alone. Tha-PA90 was found within A549 cells' cytosol with no discernible cytotoxic effects. Furthermore, Tha-PA90 administration extended the lifespan of A. baumannii-infected mice, reducing bacterial loads in major organs by up to 3 logs. Additionally, it decreased proinflammatory cytokine levels (TNF-α and IL-6), reducing the risk of sepsis from rapid bacterial lysis. Our findings indicate that Tha-PA90 is a promising solution for combating drug-resistant A. baumannii. Its enhanced efficacy, low cytotoxicity, and reduction of proinflammatory responses render it a potential candidate for infection control.
  
  Conclusions
  This study underscores the significance of engineered endolysins in addressing the pressing challenge of drug-resistant pathogens and offers insights into improved infection management strategies.
• 中文關鍵字：
• 英文關鍵字： Endolysin, Thanatin, Tha-PA90, Designed endolysin, A. baumannii infection, Drug-resistant gram-negative pathogen