抗分枝杆菌多肽杀菌作用的比较和优化研究

Mycobacterium is a common kind of pathogens that can cause skin infections, such as cutaneous tuberculosis, leprosy and non tuberculosis mycobacterium diseases. More attention has been paid to the drug resistance of mycobacteria in recent years. Antimicrobial peptide is a kind of amphiphilic cationic peptides extensively existing in organisms and has a broad-spectrum antibacterial activity, rapid onset, less resistance, low or no toxicity for host cells. Antimicrobial peptides are showing great promise for the development of next-generation antibiotics. Current research has presented that the antimicrobial peptide LL-37, defensins and IL-26 have a bactericidal activity against mycobacterial. However, whether different immune conditions and different kinds of mycobacterium have the impact on the bactericidal activity of antimicrobial peptides or not need systematic evaluation. The mechanisms of antimicrobial activity remain not fully understood. The objectives of this study are: (1) establishment of methods of in vitro killing efficiency tests for mycobacteria and antimicrobial peptides; (2) evaluation of bactericidal activity of antimicrobial peptides among different mycobacterium; (3) evaluation of bactericidal activity of antimicrobial peptides under different immune conditions; (4) clarification of the antimicrobial mechanisms of antibacterial peptides, selection and optimization of antimicrobial peptides based on the bactericidal activity. Based on the above studies, we could further explain the direct or indirect bactericidal mechanisms, select and optimize the antimicrobial peptide to acquire a better effectiveness and safety and provide a new idea or target for mycobacterial therapy.

分枝杆菌是临床常见的一类致病菌，可引起皮肤结核、麻风病和非结核分枝杆菌皮肤感染。近年来分枝杆菌的耐药问题越来越引起重视。而抗菌肽是一类普遍存在于生物体内的双亲性阳离子短肽，具有抗菌谱广，杀菌迅速，耐药现象少，对宿主细胞无毒或低毒性，有望作为药物治疗开发的新方向。目前已有研究发现抗菌肽LL-37、防御素以及IL-26对分枝杆菌具有杀伤作用，但是在不同免疫条件下、针对不同种类的分枝杆菌尚缺乏系统性的比较研究，对其具体抗菌机制也尚未完全清楚。本课题拟：（1）建立分枝杆菌和抗菌肽的体外药物敏感性实验平台；（2）评价不同种类分枝杆菌对抗菌肽的体外敏感性差异；（3）比较不同免疫条件下不同分枝杆菌对抗菌肽的敏感性差异；（4）探索抗菌肽的抗菌机制，依据抗菌能力对抗菌肽进行比较、筛选和优化。通过上述研究进一步明确其直接和间接抗菌机制，筛选、优化获取高效安全的抗菌多肽，为治疗分枝杆菌感染提供新的思路和靶点。

分枝杆菌感染是一种临床较为常见的感染性皮肤病，近年来分枝杆菌的耐药问题越来越引起重视。不同于传统抗生素，抗菌肽是一类普遍存在于生物体内的双亲性阳离子短肽，具有抗菌谱广，杀菌迅速，耐药现象少，对宿主细胞无毒或低毒性。因此，该课题进行抗菌肽对分枝杆菌的杀伤作用和机制研究。课题选取了IL-26，LL-37以及防御素。主要研究内容包括建立分枝杆菌和抗菌肽的体外药物敏感性实验平台，评价不同免疫模型中分枝杆菌对不同药物体外药物敏感性差异，探索了不同免疫条件下不同抗菌肽杀菌机制的差异，评价免疫细胞对抗菌肽杀菌能力的影响。通过研究发现IL-26的杀菌效果较好，对麻风等多种分枝杆菌均有杀伤作用。其杀伤机制是通过对菌体胞膜进行打孔，造成局部缺失发挥抗菌作用。另外还可能通过与细胞和免疫分子之间相互作用从而间接发挥抗菌作用。下一步IL-26有望通过进一步结构优化修饰，更安全高效，为治疗分枝杆菌感染提供新的选择。