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Methicillin-resistant  Staphylococcus aureus  (MRSA) is a widespread pathogen, often causing recurrent and deadly infections in the hospital and community. Many  S. aureus  virulence factors have been suggested as potential targets for antivirulence therapy to decrease the threat of diminishing antibiotic availability. Antivirulence methods hold promise due to their adjunctive and prophylactic potential and decreased risk for selective pressure. This review describes the dominant virulence mechanisms exerted by MRSA and antivirulence therapeutics that are currently undergoing testing in clinical or preclinical stages. We also discuss the advantages and downsides of several investigational antivirulence approaches, including the targeting of bacterial transporters, host-directed therapy, and quorum-sensing inhibitors. For this review, a systematic search of literature on PubMed, Google Scholar, and Web of Science for relevant search terms was performed in April and May 2023. Vaccine and antibody strategies have failed in clinical trials and could benefit from more basic science-informed approaches. Antivirulence-targeting approaches need to be set up better to meet the requirements of drug development, rather than only providing limited results to provide ‘proof-of-principle’ translational value of pathogenesis research. Nevertheless, there is great potential of such strategies and potential particular promise for novel probiotic approaches.

Understanding mechanisms of virulence in MRSA: implications for antivirulence treatment strategies