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

Du, J.; Meile, S.; Baggenstos, J.; Jaeggi, T.; Piffaretti, P.; Hunold, L.; Matter, C. I.; Leitner, L.; Kessler, T. M.; Loessner, M. J.; Kilcher, S.; Dunne, M.

doi:10.1101/2022.03.09.483629

bioRxiv · 10.1101/2022.03.09.483629

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

Du, J.·Meile, S.·Baggenstos, J.·Jaeggi, T.·Piffaretti, P.·Hunold, L.·Matter, C. I.·Leitner, L.·Kessler, T. M.·Loessner, M. J.·Kilcher, S.·Dunne, M.

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Abstract

Bacteriophages operate via pathogen-specific mechanisms of action distinct from conventional, broad-spectrum antibiotics and are emerging as promising alternatives. However, phage-mediated killing is often limited by bacterial resistance development (1,2). 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 a phage-based companion diagnostic (3), 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.

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Du, J., Meile, S., Baggenstos, J., Jaeggi, T., Piffaretti, P., Hunold, L., Matter, C. I., Leitner, L., Kessler, T. M., Loessner, M. J., Kilcher, S., Dunne, M.. 2022-03-09. Enhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors. https://doi.org/10.1101/2022.03.09.483629

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