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

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...

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Published inNature biotechnology Vol. 42; no. 2; pp. 265 - 274
Main Authors Gencay, Yilmaz Emre, Jasinskytė, Džiuginta, Robert, Camille, Semsey, Szabolcs, Martínez, Virginia, Petersen, Anders Østergaard, 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, Hallström, Björn, Hink, Jonas, Damholt, Birgitte, Troy, Alice, Grove, Mette, Clube, Jasper, Grøndahl, Christian, Haaber, Jakob Krause, van der Helm, Eric, Zdravkovic, Milan, Sommer, Morten Otto Alexander
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.02.2024
Nature Publishing Group
Subjects
631/154
631/337
692/308/153
692/308/2778
Agriculture
Animal models
Antibiotic resistance
Antibiotics
Bacteria
Biofilms
Bioinformatics
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Blood cancer
CRISPR
E coli
Escherichia coli
Fibers
Life Sciences
Microbiomes
Phages
Tail fiber protein
Online AccessGet full text
ISSN1087-0156
1546-1696
1546-1696
DOI10.1038/s41587-023-01759-y

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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. Phage engineered with tail fibers and CRISPR–Cas reduce Escherichia coli load in animals.
AbstractList 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.
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. Phage engineered with tail fibers and CRISPR–Cas reduce Escherichia coli load in animals.
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.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.
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.Phage engineered with tail fibers and CRISPR–Cas reduce Escherichia coli load in animals.
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 Zdravkovic, Milan
Brunner, Katja
Robert, Camille
Turcu, Iszabela Cristiana
Clube, Jasper
Bryde, Tina
Gram, Aurelie
Hallström, Björn
Haaber, Jakob Krause
Bayer, Lone
Doyle, Timothy B.
Bak, Emilie Glad
Grove, Mette
Sommer, Morten Otto Alexander
Salazar, Alex
Schou, Thea Staffeldt
Eriksen, Melissa Kviesgaard
Satlin, Michael J.
Grøndahl, Christian
Carvalho, Joana
Hink, Jonas
Gencay, Yilmaz Emre
van der Helm, Eric
Troy, Alice
Pascal, Ricardo
Semsey, Szabolcs
Damholt, Birgitte
Jasinskytė, Džiuginta
Koval, Lev
de Santiago Torio, Ana
Johansen, Katja Chandelle
Smrekar, Frenk
Jessen, Lene
Petersen, Anders Østergaard
Takos, Adam
Martínez, Virginia
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/37142704$$D View this record in MEDLINE/PubMed
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Snippet Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of...
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StartPage 265
SubjectTerms 631/154
631/337
692/308/153
692/308/2778
Agriculture
Animal models
Antibiotic resistance
Antibiotics
Bacteria
Biofilms
Bioinformatics
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Blood cancer
CRISPR
E coli
Escherichia coli
Fibers
Life Sciences
Microbiomes
Phages
Tail fiber protein
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Title Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice
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