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Abstract
BackgroundThe accessory gene regulator (agr) and staphylococcal accessory regulator (sarA) play opposing roles in Staphylococcus aureus biofilm formation. There is mounting evidence to suggest that these opposing roles are therapeutically relevant in that mutation of agr results in increased biofilm formation and decreased antibiotic susceptibility while mutation of sarA has the opposite effect. To the extent that induction of agr or inhibition of sarA could potentially be used to limit biofilm formation, this makes it important to understand the epistatic relationships between these two loci.Methodology/Principal FindingsWe generated isogenic sarA and agr mutants in clinical isolates of S. aureus and assessed the relative impact on biofilm formation. Mutation of agr resulted in an increased capacity to form a biofilm in the 8325-4 laboratory strain RN6390 but had little impact in clinical isolates S. aureus. In contrast, mutation of sarA resulted in a reduced capacity to form a biofilm in all clinical isolates irrespective of the functional status of agr. This suggests that the regulatory role of sarA in biofilm formation is independent of the interaction between sarA and agr and that sarA is epistatic to agr in this context. This was confirmed by demonstrating that restoration of sarA function restored the ability to form a biofilm even in the corresponding agr mutants. Mutation of sarA in clinical isolates also resulted in increased production of extracellular proteases and extracellular nucleases, both of which contributed to the biofilm-deficient phenotype of sarA mutants. However, studies comparing different strains with and without proteases inhibitors and/or mutation of the nuclease genes demonstrated that the agr-independent, sarA-mediated repression of extracellular proteases plays a primary role in this regard.Conclusions and SignificanceThe results we report suggest that inhibitors of sarA-mediated regulation could be used to limit biofilm formation in S. aureus and that the efficacy of such inhibitors would not be limited by spontaneous mutation of agr in the human host.
Highlights
Biofilm formation is an important aspect of many Staphylococcus aureus infections including endocarditis, osteomyelitis, and infections of implanted medical devices
The results we report suggest that inhibitors of staphylococcal accessory regulator (sarA)-mediated regulation could be used to limit biofilm formation in S. aureus and that the efficacy of such inhibitors would not be limited by spontaneous mutation of agr in the human host
The impact of agr on biofilm formation We previously demonstrated that clinical isolates of S. aureus generally form a more robust biofilm than the 8325-4 laboratory strain RN6390 and that biofilm formation in the latter is enhanced by mutation of agr [10]
Summary
Biofilm formation is an important aspect of many Staphylococcus aureus infections including endocarditis, osteomyelitis, and infections of implanted medical devices This is true with respect to the pathogenesis of the infection itself and with respect to antimicrobial therapy. The presence of a biofilm limits the efficacy of antimicrobial therapy to the point that surgical intervention is often required to remove infected tissues and/or implanted devices [1] For this reason, a considerable research effort has been aimed at defining the mechanistic basis of S. aureus biofilm formation. We chose to focus on the accessory gene regulator (agr) and the staphylococcal accessory regulator (sarA) because both of these loci have been shown to play central roles in S. aureus regulatory circuits that includes important but generally opposing roles in biofilm formation. To the extent that induction of agr or inhibition of sarA could potentially be used to limit biofilm formation, this makes it important to understand the epistatic relationships between these two loci
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