研究揭示如何应用噬菌体溶解素进行工程操作来杀灭革兰氏阴性

噬菌体是一种可以感染细菌具有多产能力的病毒，随着噬菌体感染细菌zui终可以引起大多数细菌的死亡。自从噬菌体在1910年被发现以来，其用于治疗细菌感染的潜力被许多科学家不断发掘着;当然目前来说噬菌体疗法刚刚起步，但是随着小分子抗生素的价格越来越便宜而且治疗细菌感染的效力越来越大，噬菌体疗法就慢慢被忽略了。
近年来随着抗生素耐药菌株的不断出现，噬菌体疗法又被提上议程，这使得科学家们对于此疗法的前景抱有很大希望。已有研究者使用称为细胞溶解素的噬菌体衍生蛋白质作为制剂来清除体内的革兰氏阴性致病菌感染，如治疗肺炎链球菌和炭疽杆菌感染等。
在文章中，研究者分离观察到了鼠疫杆菌毒素蛋白的晶体结构，并且揭示了如何对噬菌体溶解素进行工程操作来杀灭革兰氏阴性菌，这种鼠疫杆菌毒素蛋白称为鼠疫巴氏菌素，属于细菌毒素蛋白家族的一种。研究中，研究者Susan报道说，他们使用了工程改造的细胞溶解素来直接杀灭革兰氏阴性菌，研究者识别并分离出了鼠疫巴氏菌素的结构，并且用其引导并改造工程化的杂种细胞溶解素。鼠疫巴氏菌素包括两个结构域：结合FyuA的靶点(FyuA是鼠疫巴氏菌素的外膜蛋白，扮演着其受体的作用);另一个结构域为降解肽聚糖。这种工程改造的杂种细胞溶解素包括T4溶菌酶，一种原型的溶菌素，可以吸附至FyuA的靶点结构域上。研究者表示这种杂种细胞溶解素(细胞溶解酶)可以横过细菌的外膜蛋白，并且zui终杀死细菌菌体。而且这种细胞溶解酶的行为并不受Pim影响，Pim是一种鼠疫杆菌产生的蛋白质，可以抑制肽多糖降解酶类。因此研究者的研究结果zui终揭示了其可以抑制并且杀死表达FyuA的革兰氏阴性菌菌体。
Structural engineering of a phage lysin that targets Gram-negative pathogens
Petra Lukacika, Travis J. Barnarda, Paul W. Kellerb, Kaveri S. Chaturvedic, Nadir Seddikia, James W. Fairmana, Nicholas Noinaja, Tara L. Kirbya, Jeffrey P. Hendersonc, Alasdair C. Stevenb, B. Joseph Hinnebuschd, and Susan K. Buchanana,1
Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against Gram-positive organisms but not against Gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a β-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminay eliminating natural gut flora.