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

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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalNature Biotechnology
ISSN1087-0156
DOIs
Publication statusAccepted/In press - 2024

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