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Bacteriophage discovery to advance biotechnology and biotherapeutics

Nature Reviews Microbiology (2023)Cite this article

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This Genome Watch explores how large-scale microbiome studies are facilitating discoveries in bacteriophage biology and functional capabilities that are prime for translation towards advances in biotechnology and biotherapeutics.

Work by Adler et al.2 describes a 2-step in vitro technique for efficient genome editing of phages involving the broad-spectrum bacterial CRISPR–Cas13a. Cas13 effectors are RNA-guided RNA nucleases with catalytic activity against 2 higher eukaryotic and prokaryotic nucleotide-binding domains. The authors elegantly demonstrated how the Cas13a system from Leptotrichia buccalis can undergo homologous recombination and an enrichment process to produce markerless genome edits in bacteriophages. These Cas13 effectors are potent RNA-guided anti-phage systems despite being one of the rarest CRISPR–Cas systems identified to date. For example, Cas13a from L. buccalis was tested against 9 phylogenetically distant Escherichia coli phages, with edits ranging from small codon replacements to large multi-gene deletion mutations demonstrating Cas13a as a generalizable genome editing tool for modifying phages. This enables the engineering of phages (whether lytic or temperate) towards desired phenotypes, and carrying targeted functional genes, for applications in microbiome-based therapeutics. However, clinical applications of phages are currently restricted to emergency use as adjunctive phage therapy to treat patients with multidrug-resistant bacterial infections. For example, 20 patients were administered lytic phages either intravenously and/or through aerosolization on a compassionate-use basis to treat drug-resistant, non-tuberculosis Mycobacterium infections3. Eleven patients responded favourably, both clinically and microbiologically; notably, the authors report no resistance to phages, and no adverse effects for the patients during therapy, irrespective of the target mycobacterial species, phage type or delivery route. Furthermore, a study assessing a patient’s microbiome during systemic phage therapy to treat a staphylococcal device infection showed no significant changes to the composition of the gut and oral microbiomes (microbiota and metabolite profiles), which suggests that ecological impacts are minimal and perhaps microbiome sparing4. Given the high selectivity of phages for their bacterial hosts, limited off-target effects, and the ever-expanding functional repertoire as revealed through large-scale metagenomic studies, the landscape for molecular engineering that facilitates microbiome-based solutions is prime for phage applications.

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References

  1. Al-Shayeb, B. et al. Clades of huge phages from across Earth’s ecosystems. Nature 578, 425–431 (2020).

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  2. Adler, B. A. et al. Broad-spectrum CRISPR-Cas13a enables efficient phage genome editing. Nat. Microbiol. 7, 1967–1979 (2022).

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  3. Dedrick, R. M. et al. Phage therapy of Mycobacterium infections: compassionate use of phages in 20 patients with drug-resistant mycobacterial disease. Clin. Infect. Dis. 76, 103–112 (2023).

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  4. Mu, A. et al. Assessment of the microbiome during bacteriophage therapy in combination with systemic antibiotics to treat a case of staphylococcal device infection. Microbiome 9, 92 (2021).

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  1. Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    Andre Mu & Trevor D. Lawley

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  1. Andre Mu
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  2. Trevor D. Lawley
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Correspondence to Andre Mu.

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T.D.L. is the co-founder and CSO of Microbiotica.

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Mu, A., Lawley, T.D. Bacteriophage discovery to advance biotechnology and biotherapeutics. Nat Rev Microbiol (2023). https://doi.org/10.1038/s41579-023-00870-w

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  • DOI: https://doi.org/10.1038/s41579-023-00870-w

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