The ongoing crisis of antimicrobial resistance underscores the urgent need for disruptive innovation in the field of antibiotic development. While traditional small molecule antibiotics have saved countless lives, their efficacy is increasingly compromised by the emergence, spread, and accumulation of resistance mechanisms. In this context, phage lysins emerge as a promising class of non-traditional antibacterials, possessing unique features such as microbiome-friendliness and a low likelihood of provoking resistance. Phage lysins are enzymes produced by bacteriophages during their replication within infected bacterial cells. These enzymes specifically target the bacterial cell wall, leading to its degradation and subsequent release of newly formed phage particles. Unlike conventional antibiotics, phage lysins offer a novel approach to combating bacterial infections – one that minimizes the risk of resistance development. The current landscape of protein science is witnessing a revolutionary shift, driven by significant advancements in computational de novo protein design. These breakthroughs allow us to explore innovative avenues for creating precision biologicals with tailored characteristics. Capitalizing on these computational advances, we can unlock the full potential of phage lysins as disruptive innovations in the fight against antimicrobial resistance.