Next-Generation Target Discovery in ESKAPE Pathogens: An AI-Driven Framework from Omics-Based to Systems-Level...

Background: Antimicrobial resistance (AMR) among ESKAPE pathogens-Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.-represents a major global health threat and accounts for a substantial proportion of healthcare-associated infections. Their genomic plasticity and adaptive regulatory responses facilitate the rapid emergence and dissemination of resistance and virulence determinants. Artificial intelligence (AI) has emerged as a powerful approach for analyzing large-scale biological datasets and identifying molecular signatures associated with antimicrobial resistance and pathogenicity. Objectives: This review examines AI-driven frameworks for predictive target discovery in ESKAPE pathogens, focusing on approaches that leverage genomic and transcriptomic data and extend toward the integration of additional omics layers within network-based and systems-level modeling frameworks. We discuss how AI methods are evolving beyond phenotypic prediction toward more biologically interpretable inference for prioritizing resistance mechanisms, virulence determinants, and candidate antimicrobial targets. Conclusions and Future Directions: Current AI applications exploit genomic, transcriptomic, and network-level data to prioritize resistance and virulence determinants and to support antimicrobial discovery, including small molecules and antimicrobial peptides. However, integrative multi-layer modeling and comprehensive experimental validation remain limited. Future advances will depend on improved integration of complementary biological data, enhanced model interpretability, and robust translational validation frameworks to enable clinically actionable AI-guided novel pathogen-targeted next-generation diagnostics, therapeutic and stewardship strategies against ESKAPE pathogens.