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We previously determined the extent to which mutations of differentStaphylococcus aureus regulatory loci impact biofilm formation as assessed underin vitro conditions. Here we extend these studies to determine the extent to which those regulatory loci that had the greatest effect on biofilm formation also impact antibiotic susceptibility. The experiments were done underin vitro andin vivo conditions using two clinical isolates ofS. aureus (LAC and UAMS-1) and two functionally diverse antibiotics (daptomycin and ceftaroline). Mutation of the staphylococcal accessory regulator (sarA ) orsigB was found to significantly increase susceptibilities to both antibiotics and in both strains in a manner that could not be explained by changes in the MICs. The impact of a mutation insarA was comparable to that of a mutation insigB and greater than the impact observed with any other mutant. These results suggest that therapeutic strategies targetingsarA and/orsigB have the greatest potential to facilitate the ability to overcome the intrinsic antibiotic resistance that definesS. aureus biofilm-associated infections.

Regulatory Mutations Impacting Antibiotic Susceptibility in an Established Staphylococcus aureus Biofilm