Data mining reveals the diversity of prophage endolysins targeting pathogenic enterococci
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Antimicrobial resistance (AMR) poses a critical global health threat, with enterococci among the leading contributors due to their intrinsic and acquired resistance to antibiotics. Clinically relevant species, including Enterococcus faecalis and Enterococcus faecium , as well as the emerging poultry pathogen Enterococcus cecorum , highlight the need for alternative therapeutics across human and agricultural settings. Bacteriophages and their derived enzymes, particularly endolysins, offer promising antibacterial strategies but challenges such as phage resistance and limited lysin diversity hinder their application. In this study, we performed a large-scale analysis of prophage-encoded endolysins across these three enterococcal opportunistic pathogens, characterizing over 48,000 sequences. We identified 33 distinct domain architectures combining diverse catalytic and cell wall-binding domains, including novel putative cell wall binding domains. These findings expand the known diversity of enterococcal lysins and provide a comprehensive resource for the rational design of stable, recombinant “enzybiotics” to combat multidrug-resistant enterococcal infections.
Data summary
All genomes analysed in this work are available through Genbank. The data mining strategy was carried out open-access software available through GitHub as described in the Methods section. The raw output of the search and sequences obtained after each filtering step are provided in Supplementary Files 1 and 2. Modelling data related to figure 6 is provided in supplementary File 3.
Impact statement
Antimicrobial resistant enterococci threaten therapeutic options in both medicine and agriculture. Yet, the therapeutic potential of bacteriophage-derived endolysins (enzybiotics) is limited by an incomplete understanding of their natural diversity. By analysing more than 48,000 prophage encoded lysins from E. faecalis, E. faecium , and E. cecorum , this study provides the most extensive characterization of enterococcal lysin architectures to date. The identification of 34 distinct domain organizations, including a previously unrecognized cell wall–binding domain, substantially broadens the known functional repertoire of these enzymes. This work fills a major knowledge gap and offers a foundational resource for engineering stable, targeted enzybiotics to combat multidrug resistant enterococcal infections.
