학술논문
Engineered phage with antibacterial CRISPR-Cas selectively reduce E. coli burden in mice.
Document Type
Academic Journal
Author
Gencay YE; SNIPR BIOME ApS, Copenhagen, Denmark.; Jasinskytė D; SNIPR BIOME ApS, Copenhagen, Denmark.; Robert C; SNIPR BIOME ApS, Copenhagen, Denmark.; Semsey S; SNIPR BIOME ApS, Copenhagen, Denmark.; Martínez V; SNIPR BIOME ApS, Copenhagen, Denmark.; Petersen AØ; SNIPR BIOME ApS, Copenhagen, Denmark.; Brunner K; SNIPR BIOME ApS, Copenhagen, Denmark.; de Santiago Torio A; SNIPR BIOME ApS, Copenhagen, Denmark.; Salazar A; SNIPR BIOME ApS, Copenhagen, Denmark.; Turcu IC; SNIPR BIOME ApS, Copenhagen, Denmark.; Eriksen MK; SNIPR BIOME ApS, Copenhagen, Denmark.; Koval L; SNIPR BIOME ApS, Copenhagen, Denmark.; Takos A; SNIPR BIOME ApS, Copenhagen, Denmark.; Pascal R; SNIPR BIOME ApS, Copenhagen, Denmark.; Schou TS; SNIPR BIOME ApS, Copenhagen, Denmark.; Bayer L; SNIPR BIOME ApS, Copenhagen, Denmark.; Bryde T; SNIPR BIOME ApS, Copenhagen, Denmark.; Johansen KC; SNIPR BIOME ApS, Copenhagen, Denmark.; Bak EG; SNIPR BIOME ApS, Copenhagen, Denmark.; Smrekar F; JAFRAL, Ljubljana, Slovenia.; Doyle TB; JMI Laboratories, North Liberty, IA, USA.; Satlin MJ; Division of Infectious Diseases, Weill Cornell Medicine, New York City, NY, USA.; Gram A; SNIPR BIOME ApS, Copenhagen, Denmark.; Carvalho J; SNIPR BIOME ApS, Copenhagen, Denmark.; Jessen L; SNIPR BIOME ApS, Copenhagen, Denmark.; Hallström B; SNIPR BIOME ApS, Copenhagen, Denmark.; Hink J; SNIPR BIOME ApS, Copenhagen, Denmark.; Damholt B; SNIPR BIOME ApS, Copenhagen, Denmark.; Troy A; SNIPR BIOME ApS, Copenhagen, Denmark.; Grove M; SNIPR BIOME ApS, Copenhagen, Denmark.; Clube J; SNIPR BIOME ApS, Copenhagen, Denmark.; Grøndahl C; SNIPR BIOME ApS, Copenhagen, Denmark.; Haaber JK; SNIPR BIOME ApS, Copenhagen, Denmark.; van der Helm E; SNIPR BIOME ApS, Copenhagen, Denmark.; Zdravkovic M; SNIPR BIOME ApS, Copenhagen, Denmark.; Sommer MOA; SNIPR BIOME ApS, Copenhagen, Denmark. ms@sniprbiome.com.; Novo Nordisk Foundation Center for Biosustainability, DTU Biosustain, Kongens Lyngby, Denmark. ms@sniprbiome.com.
Source
Publisher: Nature America Publishing Country of Publication: United States NLM ID: 9604648 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1696 (Electronic) Linking ISSN: 10870156 NLM ISO Abbreviation: Nat Biotechnol Subsets: MEDLINE
Subject
Language
English
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.
(© 2023. The Author(s).)
(© 2023. The Author(s).)