Staphylococcus aureus Biofilm-Associated Infections: Have We Found a Clinically Relevant Target?

Staphylococcus aureus is one of the most diverse bacterial pathogens. This is reflected in its ability to cause a wide array of infections and in genotypic and phenotypic differences between clinical isolates that extend beyond their antibiotic resistance status. Many S. aureus infections, including those involving indwelling medical devices, are therapeutically defined by the formation of a biofilm. This is reflected in the number of reports focusing on S. aureus biofilm formation and biofilm-associated infections. These infections are characterized by a level of intrinsic resistance that compromises conventional antibiotic therapy irrespective of acquired resistance, suggesting that an inhibitor of biofilm formation would have tremendous clinical value. Many reports have described large-scale screens aimed at identifying compounds that limit S. aureus biofilm formation, but relatively few examined whether the limitation was sufficient to overcome this intrinsic resistance. Similarly, while many of these reports examined the impact of putative inhibitors on S. aureus phenotypes, very few took a focused approach to identify and optimize an effective inhibitor of specific biofilm-associated targets. Such approaches are dependent on validating a target, hopefully one that is not restricted by the diversity of S. aureus as a bacterial pathogen. Rigorous biological validation of such a target would allow investigators to virtually screen vast chemical libraries to identify potential inhibitors that warrant further investigation based on their predicted function. Here, we summarize reports describing S. aureus regulatory loci implicated in biofilm formation to assess whether they are viable targets for the development of an anti-biofilm therapeutic strategy with an emphasis on whether sarA has been sufficiently validated to warrant consideration in this important clinical context.