Staphylococcus aureus Proteins Implicated in the Reduced Virulence of sarA and sarA/agr Mutants in Osteomyelitis
2025
Karen E. Beenken | Mara J. Campbell | Stephanie D. Byrum | Rick D. Edmondson | Samuel G. Mackintosh | Alan J. Tackett | Mark S. Smeltzer
Using a murine osteomyelitis model, we recently demonstrated that Staphylococcus aureus sarA and sarA/agr mutants generated in the USA300 strain LAC are attenuated to a greater extent than an isogenic agr mutant and that this can be attributed to a significant extent to the increased production of extracellular proteases in both mutants. Based on this, we used a mass-based proteomics approach to compare the proteomes of LAC, its isogenic agr, sarA, and sarA/agr mutants, and isogenic derivatives of all four of these strains unable to produce the extracellular proteases aureolysin, SspA, SspB, ScpA, or SplA-F. This allowed us to identify proteins that were present in reduced amounts in sarA, and sarA/agr mutants owing to the increased production of extracellular proteases. A total of 1039 proteins were detected in conditioned media (CM) from overnight cultures of LAC, and protease-mediated degradation was shown to contribute to the reduced abundance of 224 of these (21.6%) in CM from the sarA and sarA/agr mutants. Among these were specific proteins previously implicated in the pathogenesis and therapeutic recalcitrance of S. aureus osteomyelitis. This demonstrates that the ability of sarA to limit protease production plays a key role in post-translational remodeling of the S. aureus proteome to a degree that can be correlated with reduced virulence in our osteomyelitis model, and that it does so irrespective of the functional status of agr. This also suggests that at least some of these 224 proteins may be viable targets for prophylactic or therapeutic intervention.
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