| Summary: | Shigellosis is a leading global cause of diarrheal disease and travelers’ diarrhea now being complicated by the dissemination of antibiotic resistance, necessitating the development of alternative antibacterials such as therapeutic bacteriophages (phages). Phages with lytic activity against <i>Shigella</i> strains were isolated from sewage. The genomes of 32 phages were sequenced, and based on genomic comparisons belong to seven taxonomic genera: <i>Teetrevirus</i>, <i>Teseptimavirus</i>, <i>Kayfunavirus</i>, <i>Tequatrovirus</i>, <i>Mooglevirus</i>, <i>Mosigvirus</i> and <i>Hanrivervirus</i>. Phage host ranges were determined with a diverse panel of 95 clinical isolates of <i>Shigella</i> from Southeast Asia and other geographic regions, representing different species and serotypes. Three-phage mixtures were designed, with one possessing lytic activity against 89% of the strain panel. This cocktail exhibited lytic activity against 100% of <i>S. sonnei</i> isolates, 97.2% of <i>S. flexneri</i> (multiple serotypes) and 100% of <i>S. dysenteriae</i> serotypes 1 and 2. Another 3-phage cocktail composed of two myophages and one podophage showed both a broad host range and the ability to completely sterilize liquid culture of a model virulent strain <i>S. flexneri</i> 2457T. In a <i>Galleria mellonella</i> model of lethal infection with <i>S. flexneri</i> 2457T, this 3-phage cocktail provided a significant increase in survival.
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