The emerging and spreading antibiotic resistance and the unprecedented void in the discovery of novel antibiotics increasingly leads to a reduced number of therapeutic options. The once successful Waksman platform for the discovery of natural antibiotics is largely depleted. Lysins or bacteriophage-encoded peptidoglycan hydrolases are a novel, alternative class of antibiotics. They are generally highly specific at the species level and thus have a narrow spectrum. Given the natural abundance of bacteriophages, lysins can be found against any bacterium. In addition, the modular composition of lysins offers many opportunities for combinatorial shuffling of lysin domains to improve the antibacterial properties. A first lysin successfully passed a superiority clinical phase II trial and got a Breakthrough Therapy designation by the FDA. Yet, we and other experts claim that more novel lysin candidates must be discovered and engineered to feed the (pre)clinical pipeline. The goal of my PhD research proposal is to establish a highly performant discovery and engineering platform for novel lysin-based antibiotics, driven by droplet-based functional metagenomics and directed evolution with VersaTile technology. As such we aim to strengthen and to broaden the promising and clinically demonstrated potential of lysins as a novel antibiotic class that is broadly applicable to many pathogens.