近日，中科院昆明动物所研究员赖仞领导的课题组，从结核杆菌噬菌体中识别出一小分子多肽。该抗菌肽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。相关成果日前发表于《美国实验生物学学会联合会杂志》。
据介绍，结核病由人类重大病原菌结核杆菌感染引起，全球有三分之一的人口感染过结核杆菌。结核病的死亡率在单因素的感染性疾病中位居第二，每年有接近200万人死于结核病，并有900万新增感染病例。
近年来，多种可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大量应用，但多重耐药性与广泛耐药性结核杆菌菌株的大量出现，给结核病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，可有效地与宿主细菌相互作用。为此，赖仞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，甚至直接抑制或杀灭结核杆菌。
“我们从结核杆菌噬菌体中识别了小分子多肽PK34，它可专一地结合结核杆菌表面最丰富的糖酯。糖酯被称作结核杆菌的核心因子，给小鼠尾静脉注射糖酯，可全方位模拟结核杆菌感染后肺部发生的一系列免疫病理反应。因此，糖酯是研发抗结核杆菌药物的一个重要靶标。”赖仞介绍说，同时，PK34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和蛋白激酶B的活化，从而抑制发炎因子的大量分泌，并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。（生物谷Bioon.com）
doi:10.1096/fj.13-227454
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A mycobacteriophage-derived trehalose-6,6′-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities
Lin Wei*,†,1, Jing Wu*,‡,1, Han Liu*,‡,1, Hailong Yang*, Mingqiang Rong*, Dongsheng Li*, Pinghu Zhang§, Junyou Han∥,2 and Ren Lai*,†,2
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.
