(Bacterio)phage lysins are developed as enzyme-based antibacterials with an outstanding potential to fight antibiotic resistance. The lead lysin is currently evaluated under a clinical phase III trial. What sets apart lysins from all other classes of antibacterials is their modularity and the opportunities that emerge thereof to customize their antibacterial properties. Lysins therefore represent a true new class of antibacterials. Increasing efforts are done to exploit this modularity but these efforts remain empirical and require brute-force methods to identify lead lysins. In my postdoctoral fellowship proposal I aim to widen the enigmatic and superficial understanding of modular lysins in their natural role and to gain deep insights in the modularity and sequence-function relationships of lysins from an evolutionary point of view. Specifically, I aim to understand the evolutionary drift and shift processes that steer lysin evolution to optimal phage fitness and lysis kinetics, and that tune their specificity profile. Therefore, I will blend computation and experiment, and rely on recent advances in protein science (AlphaFold, ancestral reconstruction, VersaTile assembly) and synthetic biology (construction and rebooting of synthetic lytic phages) to address fundamental questions that could not be addressed before. I expect that this basic understanding will leverage the translational field of engineering lysins as antibacterials.