Identifying potential novel widespread determinants of bacterial pathogenicity using phylogenetic-based orthology analysis.

Introduction: The global rise in antibiotic resistance and emergence of new bacterial pathogens pose a significant threat to public health. Novel approaches to uncover potential novel diagnostic and therapeutic targets for these pathogens are needed. Methods: In this study, we conducted a large-scale, phylogenetic-based orthology analysis (OA) to compare the proteomes of pathogenic to humans (HP) and non-pathogenic to humans (NHP) bacterial strains across 734 strains from 514 species and 91 families. Results: Using a dedicated workflow, we identified 4,383 hierarchical orthologous groups (HOGs) significantly associated with the HP label, many of which are linked to critical factors such as stress tolerance, metabolic versatility, and antibiotic resistance. Both known virulence factors (VFs) and potential novel widespread pathogenicity determinants were uncovered, supported by both statistical testing and complementary protein domain analysis. Discussion: By integrating curated strain-level pathogenicity annotations from BacSPaD with phylogeny-based OA, we introduce a novel approach and provide a novel resource for bacterial pathogenicity research.