Beyond antibiotics: Multidimensional interventions and coordinated governance against ESKAPE resistance

• This review proposes a paradigm shift from antibiotic-centric warfare to ecological co-management against Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species . • This review introduces four integrated strategies—microbiome stewardship, One Health 2.0, evolutionary control, and novel antimetabolite targeting—supported by an overarching framework for clinical translation and risk management. • This review highlights biotin biosynthesis inhibition as an innovative approach to restore polymyxin efficacy and combat pan-resistant strains. ESKAPE pathogens—including Klebsiella pneumoniae , Acinetobacter baumannii ( A. baumannii ), and Enterobacter spp . [all World Health Organization (WHO) critical priorities], as well as Staphylococcus aureus , Pseudomonas aeruginosa , and Enterococcus faecium (WHO high priority), pose a significant global health threat due to their extensive drug resistance and rapid evolutionary capacity. This article advocates a paradigm shift from conventional antibiotic warfare to “ecological co-management,” integrating four innovative four strategies plus an overarching framework: (1) microbiome-based interventions using probiotics, phages, and niche modulation; (2) a One Health 2.0 framework incorporating wastewater surveillance and artificial intelligence (AI)-driven stewardship; (3) evolutionary constraint methods including anti-virulence agents and clustered regularly interspaced short palindromic repeats (CRISPR)-based targeting; (4) metabolic pathway intervention and antimetabolite therapy such as biotin biosynthesis inhibition; (5) clinical translation and risk management system for innovative antimicrobial strategies. These multidimensional efforts aim to disrupt resistance transmission, restore antibiotic susceptibility, and promote sustainable pathogen control through ecological and systems-level integration.