耐药鲍曼不动杆菌严重威胁人类健康，开发新型抗生素迫在眉睫。人防御素5（HD5）具有抗菌活性强、不易被细菌耐受等特点，是传统抗生素的理想替代物。制备复杂和活性易受盐离子干扰是制约HD5药用开发的两个主要问题。由于防御素局部应用抗菌时无需二硫键规避酶解，本项目前期通过构效关系研究明确了以去除二硫键简化HD5合成的方案。在此基础上，拟使用生物膜干涉、菌落计数和细胞毒性实验，筛选利于简化肽在高浓度盐溶液中抗耐药鲍曼不动杆菌的分子间二硫键和正电荷氨基酸。体外实验筛选出高效简化肽后，拟使用放创-感染模型评估多肽的体内抗菌效果，用透射电镜、激光共聚焦以及细菌黏附侵袭实验探讨高效简化肽抗耐药鲍曼不动杆菌的机制。项目旨在设计出新型抗耐药鲍曼不动杆菌抗生素，推进HD5在临床感染防治方面的应用。

Drug-resistant Acinetobacter baumannii seriously threatens human health, which necessitates the development of novel antibiotics. Human defensin 5 (HD5) is a potent antibacterial peptide. Because bacteria are difficult to resist HD5, it is a promising candidate to traditional antibiotics. The complex process in peptide preparation, as well as the limited efficiency in saline solution，are two major problems slowing down the development of HD5. Because it is unnecessary for disulfide bonds to protect peptide from degradation when HD5 is locally used, disulfide removal is an instrumental method to simplify synthesis. Accordingly, this project plans to screen the right intermolecular disulfide bond and electropositive residue to enhance the bacterial killing of simplified HD5 against drug-resistant Acinetobacter baumannii in the context of high concentrations of saline solution by a structure-activity relationship study, where biolayer interferometry, bacterial colony count assay, and cytotoxicity evaluation are used. Furthermore, a Radiation-Wound-Infection model is employed to detect the antibacterial efficiency of simplified HD5 against drug-resistant Acinetobacter baumannii in vivo. TEM, laser scanning confocal, and bacterial adhesion-invasion assay are used as well to uncover the underlying antibacterial mechanism. This project is set up to design a novel antibiotic against drug-resistant Acinetobacter baumannii and promote the application of HD5 in clinic.