Phage therapy is a promising treatment option for multi-drug-resistant infections; however, successful development of phage-based therapies is hampered by the possible acquisition of resistance by bacteria. Lu and colleagues identified regions in the tail fibre of the T3 phage that dictate phage host range, termed host-range-determining regions. They genetically engineered these regions through site-directed mutagenesis in a high-throughput manner. This approach, which is analogous to antibody specificity engineering, led to the generation of synthetic ‘phagebodies’ with a broadened host range that were able to target naturally occurring phage-resistant bacterial mutants. Bacterial resistance to phagebodies was not observed. Finally, an engineered phagebody cocktail eliminated sensitive bacterial strains in a mouse skin infection model. The findings will enhance the development of phage-based antimicrobials.