FASEB J：结核杆菌噬菌体来源的抗菌肽具有抗结核功能

结核病（Tuberculosis）是由人类重大病原菌结核杆菌（Mycobacterium tuberculosis）感染引起的，全球有三分之一的人口感染过结核杆菌，全球结核病的死亡率在单因素的感染性疾病当中位居第二，每年有接近200万的人口死于结核病，而且每年有新增900万人口活动性结核杆菌感染病例，全球结核病负担严重，导致严重的全球性健康问题。近些年，多种可以有效控制结核病的药物如异烟肼、利福平、吡嗪酰胺和乙胺丁醇等在临床上得到大量应用，但由于多重耐药性（Multidrug-resistant，MDR）与广泛耐药性（Extensively drug-resistant，XDR）结核杆菌菌株的大量出现，给结核病的治疗带来了严重困难。因此，亟待开发新型抗结核药物来克服结核杆菌的耐药性问题。

噬菌体作为一种真细菌的病毒，可以有效地与宿主细菌相互作用。中国科学院昆明动物研究所赖仞研究员领导的课题组推测结核杆菌噬菌体可产生相关的功能物质与结核杆菌相互作用、甚至直接抑制或者杀灭结核杆菌。他们从结核杆菌噬菌体从识别了一小分子多肽PK34，其可以专一地结合于结核杆菌表面最丰富的糖酯（海藻糖二霉菌酸酯，Trehalose-6,6’-dimycolate，TDM）。TDM被称作结核杆菌的核心因子，给小鼠尾静脉注射TDM，可以全方位模拟结核杆菌感染后肺部发生的一系列的免疫病理反应，因此TDM是研发抗结核杆菌药物的一个重要靶标。PK34同时具有杀灭结核杆菌和抗发炎能力。体内抗结核动物模型试验表明PK34具有与利福平相当的体内清除结核杆菌的能力。PK34通过抑制丝裂原激活的蛋白激酶（mitogen-activated protein kinase，MAPK）和蛋白激酶B（protein kinase B，PKB）的活化，而抑制发炎因子的大量分泌，但同时维持一定炎症细胞因子水平以保持实验动物正常的免疫能力。

这些研究结果表明，PK34有望成为一种治疗结核杆菌感染的辅助药物，或作为研发抗结核药物的模板。PK34也是研究TDM与相应受体、信号通路之间相互作用的工具分子。该结果最近被FASEB Journal接受发表（A mycobacteriophage-derived trehalose-6,6'-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities. FASEB J. 2013 Apr 19. [Epub ahead of print]），该工作得到了国家自然科学基金委、科技部973和中科院的支持。

与结核杆菌相关的拓展阅读：

• 科学家发现结核杆菌抗癌新方法 更多信息请点击：有关结核杆菌更多资讯

A mycobacteriophage-derived trehalose-6,6'-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities

Bacteriophages, the viruses of eubacteria, have developed unique mechanisms to interact with their host bacteria. They have been viewed as potential antibacterial therapeutics. Mycobacteriophage-derived compounds may interact with Mycobacterium tuberculosis (MTB) and/or its components, such as the cord factor, trehalose-6,6'-dimycolate (TDM), which is the most abundant glycolipid produced on the surface of MTB. TDM emulsion injected intravenously into mice induces lung immunopathology that mimics many aspects of MTB infection. Thus, TDM is an important target for anti-MTB agent development. On the basis of genomics information of mycobacteriophages, 200 peptides were synthesized. Their effects on MTB, their interactions with TDM, and anti-inflammatory activities were tested. One of them (PK34) showed MTB-killing activity with a minimal inhibitory concentration of 50 μg/ml and TDM-binding ability. In a mouse model, PK34 showed comparable ability to clear MTB as rifampin did in vivo. It also exerted strong activity to inhibit MTB or TDM-induced inflammation in vivo. PK34 significantly inhibited inflammatory cytokines secretions by inactivating MAPK and PKB signals while it maintained certain proinflammatory cytokine production. It is possible to prospect for TDM-binding and/or anti-MTB peptides by mining the mycobacteriophages genome. In addition to its direct MTB-killing ability, PK34 might be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection or a template for developing antituberculosis (TB) agents because of its immunoregulative effects. As a TDM-binding peptide, PK34 may be a promising tool to study TDM's interactions with corresponding receptors and signal pathways.-Wei, L., Wu, J., Liu, H., Yang, H., Rong, M., Li, D., Zhang, P., Han, J., Lai, R.. A mycobacteriophage-derived trehalose-6,6'-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities.