Disarming MRSA through mechanism-guided repurposing of FDA-approved drugs and clinically investigated compounds

Methicillin-resistant Staphylococcus aureus remains a major global health threat in healthcare and community settings. Repurposing drugs approved by the U.S. Food and Drug Administration can shorten early discovery timelines, but in vitro antibacterial activity alone does not establish clinical feasibility. This review presents a mechanism-guided framework that extends beyond indication-based catalogs by integrating four therapeutic functions: direct antibacterial activity, antibiotic potentiation, antivirulence or pathogen-disarming activity, and host- or matrix-directed adjunctive activity. Candidates are further graded by evidence level, ranging from in vitro studies to animal infection models and human clinical evidence. Across membrane disruption, efflux inhibition, translation arrest, virulence regulation, biofilm targeting, and redox or metabolic perturbation, we evaluate representative potency data, model systems, infection-site relevance, achievable exposure, toxicity, resistance potential, and combination rationale. We also examine unsuccessful or stalled candidates to illustrate how pharmacokinetic/pharmacodynamic mismatch, host toxicity, formulation constraints, and model failure can outweigh compelling microbiological activity. Relevant literature was identified from PubMed, Google Scholar, Web of Science and Scopus up to June 2026. Investigational compounds and experimental adjuncts are identified separately from approved drugs. This integrated framework supports transparent prioritization of repurposed agents and the rational design of clinically plausible anti-MRSA combinations.