细菌耐药性已成为全球卫生的最大威胁之一，革兰阴性菌耐药性尤为严峻。当前对多种革兰阴性菌缺乏有效治疗方案，研发抗革兰阴性菌的新型药物已迫在眉睫。研究作用于新靶点、不易产生细菌耐药性的生物大分子是抗菌药物研究的新突破口。多靶点药物是创新药物设计的前沿策略，协同抗菌作用是遏制细菌耐药性的新趋势。本项目前期研究已发现双靶点抗菌肽-裂解酶蛋白SMAP29-LysPA26有协同抗革兰阴性菌的作用，在此基础上将深入研究SMAP29-LysPA26协同抗革兰阴性菌机理，理性设计双靶点新型抗菌肽-裂解酶协同抗菌蛋白，筛选获得一系列高抗菌活性的双靶点新型抗菌肽-裂解酶蛋白分子。本项目的实施有望阐明双靶点抗菌肽-裂解酶协同抗革兰阴性菌的新机制，获得具有自主知识产权的高抗菌活性的双靶点新型抗菌蛋白，建立双靶点协同抗革兰阴性菌的蛋白理性设计的新策略与方法，为突破抗革兰阴性菌创新药物研究的瓶颈提供重要科学依据。

Antibiotic resistance is one of the biggest threats to global health, and the Gram-negative antibiotic resistance is particularly severe. Due to the lack of effective treatments for a variety of Gram-negative bacteria infections, new antibacterial drugs to control drug-resistant Gram-negative bacteria infections are urgently needed. Biomacromolecules that act on new targets and limit the development of bacterial resistance are new breakthroughs in antimicrobial research. Designing multi-targeted drugs are the frontier strategies for innovative drug research, and combination antibiotic therapy is a new trend to combat antimicrobial resistance. We have found that the dual-targeted antimicrobial-peptide-endolysin protein SMAP29-LysPA26 has synergistic activity against Gram-negative bacteria. Based on the preliminary research, we will study the mechanism of synergistic activity against gram-negative bacteria of SMAP29-LysPA26; rationally design new dual-targeted antimicrobial-peptide-endolysin synergistic antibacterial proteins validate and obtain a series of synergistic antibacterial proteins with high antibacterial activity and excellent durability. Upon the implementation of this project, we will elucidate the new mechanism of dual-targeted antimicrobial-peptide-endolysin protein against Gram-negative bacteria, and obtain a series of synergistic antibacterial proteins with high antibacterial activity and excellent durability, to which we have independent intellectual property rights. We will establish a strategy for protein rational design against Gram-negative bacteria. The methods developed in this project will provide an important scientific basis for breaking through the bottleneck of innovative drug research against Gram-negative bacteria.