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Using CRISPR to make phages more deadly to E. coli

Using CRISPR to make phages more deadly to Escherichia coli
Tail fiber engineering. a, EoP results of LPS-dependent WT α15, Tsx-dependent WT α17 and engineered CAP α15.2 that consolidates both WT phages’ receptors. Presented titers (PFU ml−1) were obtained from independent biological triplicates as dots, with averages illustrated as bars. b–d, Lawn kill assay results of E. coli are shown as boxplots, whiskers indicate maximum and minimum values, box bounds indicate 25th and 75th percentile, with center line indicating the median; b1460 (b), b1475 (c), b1813 (d) with phages WT α15 and CAP α15.2. Significances *P < 0.05 and ***P < 0.001, P values (two-sided Mann–Whitney U test) were calculated from two independent biological duplicates comprised of ten replicates. Holm’s method adjusted P values are 1.59 × 10−7, 3.36 × 10−2 and 1.6 × 10−7 for b1460, b1475 and b1813, respectively. Distribution of 10 EoP profiles of survivor colonies purified from WT α15 lawn kill assay (b–d insets). Resistant, no plaque formation with tested phage; sensitive, EoP similar to that of parental strain; reduced, EoP (>1–2 log10) lower than that of the parental strain. Credit: Nature Biotechnology (2023). DOI: 10.1038/s41587-023-01759-y

A team of bioengineers at SNIPR BIOME ApS, in Denmark, working with one colleague from AFRAL, Ljubljana, in Slovenia and another with JMI Laboratories in the U.S., has developed a way to use the gene editing tool CRISPR to edit viruses in a way that makes phages more deadly to a range of Escherichia coli (E. coli) bacteria. In their study, reported in the journal Nature Biotechnology, the group used the gene editing tool to allow viruses to target specific bacteria in test pigs.

Over the past several years, it has become clear to the medical establishment that new types of therapies are required to fight bacterial infections. In addition to the problem of becoming more resistant to the antimicrobial therapies that have been developed, there is the problem of the slash-and-burn approach involved with antibacterial use—they cannot be used to kill only the target bacteria because they kill all the bacteria in the gut, even beneficial strains.

One new approach involves using phages, which are viruses that attack and kill bacteria. Phages must either be found or created. Finding phages that attack and kill only the target bacteria is difficult, to say the least. For that reason, the second option has become a more serious research target.

Phages cannot be created from scratch, of course, they must already exist in another form and be altered to suit a given need. Such engineering can be done in several ways. In this new effort, the researchers opted to use the CRISPR gene editing system. They began their effort by screening 162 phages for attributes that would make them more likely to infect a certain kind of bacteria: E. coli. Eventually, they whittled that number down to just eight. They then engineered each of the phages to carry that encode the gene editor, along with RNA for targeting the right genes. The team then tested the phages to see how well they targeted and killed E. coli bacteria in test minipigs.

They found that grouping several of the engineered phages together made for the most effective approach. They named the mixture SNIPR001. Testing in minipigs showed that SNIPR001 did not cause unexpected problems and the did not make their way into the bloodstream. They did, however, attack and kill E. coli. SNIPR001 is now undergoing clinical trials.

More information: Yilmaz Emre Gencay et al, Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice, Nature Biotechnology (2023). DOI: 10.1038/s41587-023-01759-y

Journal information: Nature Biotechnology

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Citation: Using CRISPR to make phages more deadly to E. coli (2023, May 9) retrieved 2 December 2023 from
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