Beyond antibiotics: Multidimensional interventions and coordinated governance against ESKAPE resistance

ESKAPE, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. 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 strategies plus an overarching framework: (1) microbiome-based interventions using probiotics, phages, and niche modulation; (2) a One Health 2.0 framework that incorporates 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; and (5) the establishment of a 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.