A global map of receptor-binding protein compatibility for the programmable design of Klebsiella and Acinetobacter phages

The narrow host range of bacteriophages limits their application against genetically diverse bacteria, motivating rational host-range modification. Progress in programmable engineering depends on establishing design principles that determine the compatibility of possible host-recognition modules with phage scaffolds. Here, we establish a genomics-guided framework that systematically identifies compatibility-determining adapter domains in receptor-binding proteins for the rational engineering of phages to target clinically relevant pathogen populations. Applying this approach to 1,270 phage genomes infecting Acinetobacter baumannii and Klebsiella pneumoniae , we show that viral diversity is highly structured: 60% of the 2,313 receptor-binding proteins group into only 19 major clusters sharing conserved N-terminal compatibility adapters. The structurally most conserved adapters in Autographivirales are associated with diverse capsule-degrading depolymerases. Known host-specificities within single-adapter clusters target capsule types that represent up to 29% of A. baumannii and 44% of K. pneumoniae carbapenem-resistant populations. Overall, we define a global repertoire of modular host-recognition components for programmable configuration of phage therapeutics.