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Summary

Bacteriophage therapy is a tantalizing therapeutic option for anti-microbial resistant bacterial infections but is currently limited to personalized therapy due to the narrow host range of individual phages. Theoretically, cocktails incorporating numerous phages targeting all possible bacterial receptor specificities could confer broad host range. Practically, however, extensive bacterial diversity and the complexity of phage-phage interactions precludes this approach. Here, using screening protocols for identifying “complementarity groups” of phages using non-redundant receptors, we generate effective, broad-range phage cocktails that prevent emergence of bacterial resistance. Further, phage complementarity groups have characteristic interactions with particular antibiotic classes, making it possible to predict phage-antibiotic as well as phage-phage interactions. Using this strategy, we generate three phage-antibiotic cocktails, each effective against >96% of 153Pseudomonas aeruginosaclinical isolates, including when used in biofilm cultures and wound infectionsin vivo. We similarly develop effectiveStaphylococcus aureusphage-antibiotic cocktails and demonstrate the utility of combined cocktails against polymicrobial (mixedP. aeruginosa/S. aureus) cultures, highlighting the broad applicability of this approach. These studies establish a blueprint for effective, broad-spectrum phage therapy cocktails and enable off-the-shelf phage-based therapeutics for antimicrobial-resistant bacterial infections.