小柯机器人

丹麦Morten Otto Alexander Sommer研究组的最新研究发现，具有抗菌CRISPR-Cas改造的工程噬菌体选择性降低了小鼠体内的大肠杆菌负荷。2023年5月4日出版的《自然-生物技术》发表了这项成果。

为了研发出靶向多种临床相关大肠杆菌的噬菌体疗法，研究人员筛选了一个包含162种野生型（WT）噬菌体的文库，鉴定了八种覆盖广泛大肠杆菌、与细菌表面受体互补结合以及携带稳定插入片段能力的噬菌体。选定的噬菌体用尾部纤维和CRISPR-Cas进行改造，以特异性靶向大肠杆菌。研究表明工程噬菌体靶向生物膜中的细菌，减少噬菌体耐受大肠杆菌的出现，并在共培养实验中胜过其来源的WT噬菌体。

四种最互补噬菌体的组合称为SNIPR001，在小鼠模型和迷你猪中均具有良好的耐受性，并且能比其它组合更好地降低小鼠肠道中的大肠杆菌负荷。SNIPR001正在临床开发阶段，用于选择性杀死大肠杆菌，因为大肠杆菌可能会对血液系统癌症患者产生致命的感染。

研究人员表示，抗生素治疗会对微生物组产生不利影响，并会产生抗生素耐药性。

附：英文原文

Title: Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice

Author: Gencay, Yilmaz Emre, Jasinskyt, Diuginta, Robert, Camille, Semsey, Szabolcs, Martnez, Virginia, Petersen, Anders stergaard, Brunner, Katja, de Santiago Torio, Ana, Salazar, Alex, Turcu, Iszabela Cristiana, Eriksen, Melissa Kviesgaard, Koval, Lev, Takos, Adam, Pascal, Ricardo, Schou, Thea Staffeldt, Bayer, Lone, Bryde, Tina, Johansen, Katja Chandelle, Bak, Emilie Glad, Smrekar, Frenk, Doyle, Timothy B., Satlin, Michael J., Gram, Aurelie, Carvalho, Joana, Jessen, Lene, Hallstrm, Bjrn, Hink, Jonas, Damholt, Birgitte, Troy, Alice, Grove, Mette, Clube, Jasper, Grndahl, Christian, Haaber, Jakob Krause, van der Helm, Eric, Zdravkovic, Milan, Sommer, Morten Otto Alexander

Issue&Volume: 2023-05-04

Abstract: Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of clinically relevant Escherichia coli, we screened a library of 162 wild-type (WT) phages, identifying eight phages with broad coverage of E. coli, complementary binding to bacterial surface receptors, and the capability to stably carry inserted cargo. Selected phages were engineered with tail fibers and CRISPR–Cas machinery to specifically target E. coli. We show that engineered phages target bacteria in biofilms, reduce the emergence of phage-tolerant E. coli and out-compete their ancestral WT phages in coculture experiments. A combination of the four most complementary bacteriophages, called SNIPR001, is well tolerated in both mouse models and minipigs and reduces E. coli load in the mouse gut better than its constituent components separately. SNIPR001 is in clinical development to selectively kill E. coli, which may cause fatal infections in hematological cancer patients.

DOI: 10.1038/s41587-023-01759-y

Source: https://www.nature.com/articles/s41587-023-01759-y

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex