While being successful in treating acute bacterial infections, the detrimental effects of broad-spectrum antibiotics on the microbiome diversity and therefore the symbiotic relationships have become increasingly clear. A current paradigm shift in the treatment of bacterial infectious diseases focuses on conservation of the microbiome by developing microbiome-friendly antibacterials. The high specificity of lysins – bacteriophage-encoded peptidoglycan degrading enzymes with proven clinical potential – is utmost appropriate to meet these goals. In this project, I will develop a pipeline for discovery, engineering and delivery of lysins in the gut environment for pathogenic decolonization. A generic approach will be elaborated for lysins, here specifically acting against vancomycin-resistant enterococci (VRE), gut commensals that become life-threatening when they cause invasive, hard-to-treat infections. Preventive VRE decolonization in high-risk patients is considered an effective approach to suppress the risk of infection.