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

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 () and Matthew Dunne ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39612-0

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