A comprehensive review of emerging therapeutic strategies against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) remains one of the most significant multidrug-resistant bacterial pathogens responsible for a broad spectrum of infections ranging from mild skin infections to severe invasive diseases, including bacteremia, pneumonia, endocarditis, osteomyelitis, and sepsis. The rapid global dissemination of MRSA is primarily driven by the acquisition of the mecA gene encoding penicillin-binding protein 2a, which confers resistance to β-lactam antibiotics. In addition to β-lactam resistance, MRSA exhibits resistance to multiple antimicrobial classes through diverse mechanisms, including target-site mutations, efflux pumps, biofilm formation, horizontal gene transfer, and adaptive phenotypic variations. The virulence and persistence of MRSA is further enhanced by numerous virulence factors such as adhesins, toxins, immune evasion proteins, and extracellular enzymes that facilitate colonization, persistence, and host tissue damage. Biofilm formation additionally contributes to chronic infection and antibiotic tolerance. Despite the availability of conventional agents such as vancomycin, linezolid, and daptomycin, the emergence of resistant strains including vancomycin-resistant Staphylococcus aureus has significantly limited current therapeutic options. Consequently, there is an urgent need for innovative therapeutic strategies. This review comprehensively summarizes the evolution, pathogenesis, virulence mechanisms, biofilm biology, and antibiotic resistance mechanisms of MRSA, with particular emphasis on emerging therapeutic approaches. Novel strategies including antimicrobial peptides, nanomedicine, bacteriophage therapy, CRISPR-Cas systems, biomimetic nano-NETs, probiotics, monoclonal antibodies and plant-derived compounds are discussed as promising alternatives or adjuncts to conventional antibiotics. Collectively, these advances highlight the evolving landscape of MRSA management and the potential for next-generation therapeutics to overcome antimicrobial resistance challenges.