Escherichia coli present in the gastrointestinal tract can translocate to the blood and cause bacteraemia. Antibiotics like fluoroquinolones can help treat such infections, but they may damage beneficial microorganisms and contribute to the development of bacterial resistance. Therefore, other treatment options are needed. Bacteriophage therapy is an alternative for treating antibiotic-resistant infections, but its limited range of target bacteria raises doubts about its clinical use. CRISPR–Cas systems can overcome this specificity issue. In this study, Gencay et al. use phages and CRISPR–Cas to create engineered phages that target clinically relevant E. coli strains. First, the authors screened a library of wild-type phages against several E. coli strains. They chose phages with the broadest lytic activity and engineered them with a tail fibre and a type I-E CRISPR–Cas system from E. coli. They obtained a library of stable CRISPR–Cas-armed phages (CAPs) that targeted phylogenetically distant E. coli strains in vitro and in vivo. They then selected four CAPs to create the SNIPR001 cocktail, which targeted several E. coli strains, including fluoroquinolone-resistant ones, without affecting the gut microbiome. SNIPR001 decreased E. coli colonization in mice and was well tolerated in minipigs. It is currently undergoing clinical trials and shows potential as an antimicrobial therapy for resistant infections.