Identification of cell wall binding domains and repeats in Streptococcus pneumoniae phage endolysins: A molecular and diversity analysis

<i>Streptococcus pneumoniae</i> (pneumococcus) is a multidrug-resistant pathogen associated with pneumonia, otitis media, meningitis and other severe complications that are currently a global threat to human health. The World Health Organization listed <i>Pneumococcus</i> as the fourth of twelve globally prioritized pathogens. Identifying alternatives to antibiotic therapies is urgently needed to combat <i>Pneumococcus</i>. Bacteriophage-derived endolysins can be used as alternative therapeutics due to their bacterial cell wall hydrolyzing capability. In this study, <i>S. pneumoniae</i> phage genomes were screened to create a database of endolysins for molecular modelling and diversity analysis of these lytic proteins. A total of 89 lytic proteins were curated from 81 phage genomes and categorized into eight groups corresponding to their different enzymatically active (EAD) domains and cell wall binding (CBDs) domains. We then constructed three-dimensional structures that provided insights into these endolysins. Group I, II, III, V, and VI endolysins showed conserved catalytic and ion-binding residues similar to existing endolysins available in the Protein Data Bank. While performing structural and sequence analysis with template lysin, an additional cell wall binding repeat was observed in Group II lysin, which was not previously known. Molecular docking performed with choline confirmed the existence of this additional repeat. Group III endolysins showed 99.16 % similarity to LysME-EF1, a lysin derived from <i>Enterococcus faecalis</i>. Furthermore, the comparative computational analysis revealed the existence of CBDs in Group III lysin. This study provides the first insight into the molecular and diversity analysis of <i>S. pneumoniae</i> phage endolysins that could be valuable for developing novel lysin-based therapeutics.