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.Ĭurrently, conventional, small-molecule antibiotics with broad target specificity are the most effective treatments against bacterial infections. Compared to wildtype phage, a colicin E7-producing HEPT demonstrated superior control of patient E. Using phage-based companion diagnostics, we identified potential HEPT responder patients and treated their urine ex vivo. Moreover, we designed HEPTs to control polymicrobial uropathogen communities through production of effectors with cross-genus activity. 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. Here, we engineer phages for target-specific effector gene delivery and host-dependent production of colicin-like bacteriocins and cell wall hydrolases. However, phage-mediated killing is often limited by bacterial resistance development. Bacteriophages operate via pathogen-specific mechanisms of action distinct from conventional, broad-spectrum antibiotics and are emerging as promising alternative antimicrobials.
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