Background Staphylococcus aureus is a major bacterial pathogen capable of causing a range of infections in humans from gastrointestinal disease, skin and soft tissue infections, to severe outcomes such as sepsis. Staphylococcal infections in humans can be frequent and recurring, with treatments becoming less effective due to the growing persistence of antibiotic resistant S. aureus strains. Due to the prevalence of antibiotic resistance, and the current limitations on antibiotic development, an active and highly promising avenue of research has been to develop strategies to specifically inhibit the activity of virulence factors produced S. aureus as an alternative means to treat disease. Objective In this review we specifically highlight several major virulence factors produced by S. aureus for which recent advances in antivirulence approaches may hold promise as an alternative means to treating diseases caused by this pathogen. Strategies to inhibit virulence factors can range from small molecule inhibitors, to antibodies, to mutant and toxoid forms of the virulence proteins. Conclusion The major prevalence of antibiotic resistant strains of S. aureus combined with the lack of new antibiotic discoveries highlight the need for vigorous research into alternative strategies to combat diseases caused by this highly successful pathogen. Current efforts to develop specific antivirulence strategies, vaccine approaches, and alternative therapies for treating severe disease caused by S. aureus have the potential to stem the tide against the limitations that we face in the post-antibiotic era.

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21Background: Staphylococcus aureus (S. aureus) is a major human pathogen owing to 22 its arsenal of virulence factors, as well as its acquisition of multi-antibiotic resistance. 23Here we report the identification of a Streptolysin S (SLS) like biosynthetic gene cluster 24 in a highly virulent community-acquired methicillin resistant S. aureus (MRSA) isolate, 25 JKD6159. Examination of the SLS-like gene cluster in JKD6159 shows significant 26 homology and gene organization to the SLS-associated biosynthetic gene (sag) cluster 27 responsible for the production of the major hemolysin SLS in Group A Streptococcus. 28 Results: We took a comprehensive approach to elucidating the putative role of the sag 29 gene cluster in JKD6159 by constructing a mutant in which one of the biosynthesis 30 genes (sagB homologue) was deleted in the parent JKD6159 strain. Assays to evaluate 31 bacterial gene regulation, biofilm formation, antimicrobial activity, as well as complete 32 host cell response profile and comparative in vivo infections in Balb/Cj mice were 33 conducted. 34 Conclusions: Although no significant phenotypic changes were observed in our 35assays, we postulate that the SLS-like toxin produced by this strain of S. aureus may be 36 a highly specialized virulence factor utilized in specific environments for selective 37 advantage; studies to better understand the role of this newly discovered virulence 38 factor in S. aureus warrant further investigation. 39