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Enhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors

Author

Listed:
  • Jiemin Du

    (ETH Zurich)

  • Susanne Meile

    (ETH Zurich)

  • Jasmin Baggenstos

    (ETH Zurich)

  • Tobias Jäggi

    (ETH Zurich)

  • Pietro Piffaretti

    (ETH Zurich)

  • Laura Hunold

    (ETH Zurich)

  • Cassandra I. Matter

    (ETH Zurich)

  • Lorenz Leitner

    (University of Zurich)

  • Thomas M. Kessler

    (University of Zurich)

  • Martin J. Loessner

    (ETH Zurich)

  • Samuel Kilcher

    (ETH Zurich)

  • Matthew Dunne

    (ETH Zurich)

Abstract

Bacteriophages operate via pathogen-specific mechanisms of action distinct from conventional, broad-spectrum antibiotics and are emerging as promising alternative antimicrobials. However, phage-mediated killing is often limited by bacterial resistance development. Here, we engineer phages for target-specific effector gene delivery and host-dependent production of colicin-like bacteriocins and cell wall hydrolases. Using urinary tract infection (UTI) as a model, we show how heterologous effector phage therapeutics (HEPTs) suppress resistance and improve uropathogen killing by dual phage- and effector-mediated targeting. Moreover, we designed HEPTs to control polymicrobial uropathogen communities through production of effectors with cross-genus activity. Using phage-based companion diagnostics, we identified potential HEPT responder patients and treated their urine ex vivo. Compared to wildtype phage, a colicin E7-producing HEPT demonstrated superior control of patient E. coli bacteriuria. Arming phages with heterologous effectors paves the way for successful UTI treatment and represents a versatile tool to enhance and adapt phage-based precision antimicrobials.

Suggested Citation

  • Jiemin Du & Susanne Meile & Jasmin Baggenstos & Tobias Jäggi & Pietro Piffaretti & Laura Hunold & Cassandra I. Matter & Lorenz Leitner & Thomas M. Kessler & Martin J. Loessner & Samuel Kilcher & Matth, 2023. "Enhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39612-0
    DOI: 10.1038/s41467-023-39612-0
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    References listed on IDEAS

    as
    1. Hannah G. Hampton & Bridget N. J. Watson & Peter C. Fineran, 2020. "The arms race between bacteria and their phage foes," Nature, Nature, vol. 577(7790), pages 327-336, January.
    2. Susanne Meile & Jiemin Du & Samuel Staubli & Sebastian Grossmann & Hendrik Koliwer-Brandl & Pietro Piffaretti & Lorenz Leitner & Cassandra I. Matter & Jasmin Baggenstos & Laura Hunold & Sonja Milek & , 2023. "Engineered reporter phages for detection of Escherichia coli, Enterococcus, and Klebsiella in urine," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
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    1. Susanne Meile & Jiemin Du & Samuel Staubli & Sebastian Grossmann & Hendrik Koliwer-Brandl & Pietro Piffaretti & Lorenz Leitner & Cassandra I. Matter & Jasmin Baggenstos & Laura Hunold & Sonja Milek & , 2023. "Engineered reporter phages for detection of Escherichia coli, Enterococcus, and Klebsiella in urine," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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