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 Smrekar; Timothy 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

doi:10.1038/s41587-023-01759-y

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

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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 language	English
Journal	Nature Biotechnology
Volume	42
Pages (from-to)	265–274
ISSN	1087-0156
DOIs	https://doi.org/10.1038/s41587-023-01759-y
Publication status	Published - 2024

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Gencay, Y. E., Jasinskytė, D., Robert, C., Semsey, S., Martínez, V., Petersen, A. Ø., Brunner, K., de Santiago Torio, A., Salazar, A., Turcu, I. C., Eriksen, M. K., Koval, L., Takos, A., Pascal, R., Schou, T. S., Bayer, L., Bryde, T., Johansen, K. C., Bak, E. G., ... Sommer, M. O. A. (2024). Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice. Nature Biotechnology, 42, 265–274. https://doi.org/10.1038/s41587-023-01759-y

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title = "Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice",

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.",

author = "Gencay, \{Yilmaz Emre\} and D{\v z}iuginta Jasinskytė and Camille Robert and Szabolcs Semsey and Virginia Mart{\'i}nez and Petersen, \{Anders {\O}stergaard\} and Katja Brunner and \{de Santiago Torio\}, Ana and Alex Salazar and Turcu, \{Iszabela Cristiana\} and Eriksen, \{Melissa Kviesgaard\} and Lev Koval and Adam Takos and Ricardo Pascal and Schou, \{Thea Staffeldt\} and Lone Bayer and Tina Bryde and Johansen, \{Katja Chandelle\} and Bak, \{Emilie Glad\} and Frenk Smrekar and Doyle, \{Timothy B.\} and Satlin, \{Michael J.\} and Aurelie Gram and Joana Carvalho and Lene Jessen and Bj{\"o}rn Hallstr{\"o}m and Jonas Hink and Birgitte Damholt and Alice Troy and Mette Grove and Jasper Clube and Christian Gr{\o}ndahl and Haaber, \{Jakob Krause\} and \{van der Helm\}, Eric and Milan Zdravkovic and Sommer, \{Morten Otto Alexander\}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2024",

doi = "10.1038/s41587-023-01759-y",

language = "English",

volume = "42",

pages = "265–274",

journal = "Nature Biotechnology",

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Gencay, YE, Jasinskytė, D, Robert, C, Semsey, S, Martínez, V, Petersen, AØ, Brunner, K, de Santiago Torio, A, Salazar, A, Turcu, IC, Eriksen, MK, Koval, L, Takos, A, Pascal, R, Schou, TS, Bayer, L, Bryde, T, Johansen, KC, Bak, EG, Smrekar, F, Doyle, TB, Satlin, MJ, Gram, A, Carvalho, J, Jessen, L, Hallström, B, Hink, J, Damholt, B, Troy, A, Grove, M, Clube, J, Grøndahl, C, Haaber, JK, van der Helm, E, Zdravkovic, M & Sommer, MOA 2024, 'Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice', Nature Biotechnology, vol. 42, pp. 265–274. https://doi.org/10.1038/s41587-023-01759-y

TY - JOUR

T1 - Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice

AU - Gencay, Yilmaz Emre

AU - Jasinskytė, Džiuginta

AU - Robert, Camille

AU - Semsey, Szabolcs

AU - Martínez, Virginia

AU - Petersen, Anders Østergaard

AU - Brunner, Katja

AU - de Santiago Torio, Ana

AU - Salazar, Alex

AU - Turcu, Iszabela Cristiana

AU - Eriksen, Melissa Kviesgaard

AU - Koval, Lev

AU - Takos, Adam

AU - Pascal, Ricardo

AU - Schou, Thea Staffeldt

AU - Bayer, Lone

AU - Bryde, Tina

AU - Johansen, Katja Chandelle

AU - Bak, Emilie Glad

AU - Smrekar, Frenk

AU - Doyle, Timothy B.

AU - Satlin, Michael J.

AU - Gram, Aurelie

AU - Carvalho, Joana

AU - Jessen, Lene

AU - Hallström, Björn

AU - Hink, Jonas

AU - Damholt, Birgitte

AU - Troy, Alice

AU - Grove, Mette

AU - Clube, Jasper

AU - Grøndahl, Christian

AU - Haaber, Jakob Krause

AU - van der Helm, Eric

AU - Zdravkovic, Milan

AU - Sommer, Morten Otto Alexander

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s41587-023-01759-y

DO - 10.1038/s41587-023-01759-y

M3 - Journal article

C2 - 37142704

AN - SCOPUS:85158118682

SN - 1087-0156

VL - 42

SP - 265

EP - 274

JO - Nature Biotechnology

JF - Nature Biotechnology

ER -

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

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