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

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...

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Veröffentlicht in:Nature communications 2023-07, Vol.14 (1), p.4337-4337, Article 4337
Hauptverfasser: Du, Jiemin, Meile, Susanne, Baggenstos, Jasmin, Jäggi, Tobias, Piffaretti, Pietro, Hunold, Laura, Matter, Cassandra I., Leitner, Lorenz, Kessler, Thomas M., Loessner, Martin J., Kilcher, Samuel, Dunne, Matthew
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Sprache:eng
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Zusammenfassung: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. Du et al . genetically engineer bacteriophages into heterologous effector phage therapeutics, enabling dual phage- and effector-mediated targeting for a two-pronged attack against bacterial pathogens.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-39612-0