Tamás StirlingExcited to share our new preprint on bacteriophage engineering 🦠 🎨
https://www.biorxiv.org/content/10.64898/2026.02.20.706991v1
We establish a genomics-guided approach for inferring receptor-binding protein compatibility, which may guide host retargeting of therapeutic bacteriophage scaffolds. #AMR, #phagetherapy
For the FOSS-minded folks here: we also released the R package tailor which we used for key parts of the analysis: https://github.com/sbthandras/tailor
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. ### Competing Interest Statement Balint Kintses is the founder of SplitPhage Solutions Ltd. and a shareholder in BRC-Bio Ltd., companies operating in the field of biotechnology. These companies had no role in the design, execution, interpretation, or funding of this study. National Research, Development and Innovation Fund ADVANCED, 149516 2024-1.2.2-ERA_NET-2024-00004 grant the National Laboratory of Biotechnology grant, 2022-2.1.1-NL-2022-00008 the National Laboratory for Health Security grant, RRF-2.3.1-21-2022-00006 the HUN-REN TKCS-2024/66 grant the Ministry of Culture and Innovation of Hungary grant KDP-2023-C2285907, financed under the National Research, Development and Innovation Fund, 2023-2.1.2-KDP-2023-00002 the European Unions Horizon 2020 Research and Innovation Programme, 739593
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