针对畜牧业中胞内感染严重的金黄色葡萄球菌，本项目组前期研发抗菌肽NZ2114胞内作用效果好，但因二硫键至其生产成本高、难度大、周期长。因此，本课题拟探讨二硫键对NZ2114抗菌功能与结构影响并设计出结构简化、胞内抗菌活性高、制备便捷、成本低廉的衍生肽，在此基础上进行胞外/内杀菌效果、作用机理和体内药效表征。具体拟定以下研究内容：1）探讨二硫键对抗菌活性与结构之间的定向关系，明确对其杀菌能力与结构维持具有重要作用的关键基团；2）简化二硫键结构并综合分子拼接、电荷、表面能量、疏水力矩等情况设计出胞内杀菌能力强、易于制备生产的衍生肽；3）通过衍生肽对金黄色葡萄球菌胞外/内作用效果进行药效学表征并探讨其在细胞壁前体/细胞膜/DNA水平上杀菌机理；4）研究衍生肽模式动物体内作用效果。以上研究为其在畜禽金黄色葡萄球菌胞内感染防治应用领域提供配套新型参考技术，为其替代畜禽抗生素奠定理论和应用基础。

The antimicrobial peptide NZ2114 is active against the intracellular infection of Staphylococcus aureus in livestock and poultry. However, the production process is high cost, difficulty, and long period due to the three pairs of disulfide bond. As a result, the development of high activity and low cost NZ2114 derived peptide is urgent. Based on the foundation of our group and the tendency of the animal husbandry, the aim of this work will be focused on the following four aspects: 1) the relationship of disulfide bond and antimicrobial activity of NZ2114 will be evaluated and the key groups which contribute to the structure maintaining will also be illustrated; 2) the derived peptide with enhanced activity and simplified disulfide bond structure will be designed according to the key parameters such as molecular docking, charge, surface energy and hydrophobic torque; 3) the extracellular/intracellular efforts of derived peptide and the bactericidal mechanisms in cell membranes, genomics DNA, and precursors of cell wall will also be studied; 4) In vivo effect of NZ2114 derived peptides will be evaluated in the mastitis mice infected by Staphylococcus aureus. The above results will provide the support of pharmacodynamics and pharmacokinetic background data of disulfide bond simplified peptides of NZ2114 in intracellular infection of Staphylococcus aureus, which will lay theoretical and application foundation for promoting them as new antimicrobial agents on the alternative to antibiotics.