Author:
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
Abstract
AbstractBacteriophages 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 urineex vivo. Compared to wildtype phage, a colicin E7-producing HEPT demonstrated superior control of patientE. colibacteriuria. 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.
Publisher
Cold Spring Harbor Laboratory
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