近日,，中科院昆明動物所研究員賴仞領導的課題組，從結核桿菌噬菌體中識別出一小分子多肽,。該抗菌肽有望成為一種治療結核桿菌感染的輔助藥物,，或作為研發(fā)抗結核藥物的模板。相關成果日前發(fā)表于《美國實驗生物學學會聯(lián)合會雜志》,。
據(jù)介紹,，結核病由人類重大病原菌結核桿菌感染引起，全球有三分之一的人口感染過結核桿菌,。結核病的死亡率在單因素的感染性疾病中位居第二,，每年有接近200萬人死于結核病，并有900萬新增感染病例,。
近年來,，多種可有效控制結核病的藥物，如異煙肼,、利福平,、吡嗪酰胺和乙胺丁醇等在臨床上大量應用，但多重耐藥性與廣泛耐藥性結核桿菌菌株的大量出現(xiàn),，給結核病治療帶來了嚴重困難,。因此，亟待開發(fā)新型抗結核藥物來克服結核桿菌的耐藥性問題,。
噬菌體作為一種真細菌的病毒,，可有效地與宿主細菌相互作用。為此,，賴仞課題組推測結核桿菌噬菌體可產生相關的功能物質,，與結核桿菌相互作用,，甚至直接抑制或殺滅結核桿菌。
“我們從結核桿菌噬菌體中識別了小分子多肽PK34,，它可專一地結合結核桿菌表面最豐富的糖酯,。糖酯被稱作結核桿菌的核心因子，給小鼠尾靜脈注射糖酯,，可全方位模擬結核桿菌感染后肺部發(fā)生的一系列免疫病理反應,。因此，糖酯是研發(fā)抗結核桿菌藥物的一個重要靶標,。”賴仞介紹說,，同時，PK34具有殺滅結核桿菌和抗發(fā)炎能力,。體內抗結核動物模型試驗表明,，PK34具有與利福平相當?shù)捏w內清除結核桿菌的能力。PK34通過抑制絲裂原激活的蛋白激酶和蛋白激酶B的活化,，從而抑制發(fā)炎因子的大量分泌,，并維持一定炎癥細胞因子水平以保持實驗動物正常的免疫能力。（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.
