Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation

Karen E. Beenken, Lara N. Mrak, Linda M. Griffin, Agnieszka K. Zielinska, Lindsey N. Shaw, Kelly C. Rice, Alexander R. Horswill, Kenneth W Bayles, Mark S. Smeltzer

Research output: Contribution to journalArticle

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Abstract

Background: The 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 Findings: We generated isogenic sarA and agr mutants in clinical isolates of S. aureus and assessed the relative impact on biofilmformation. Mutation of agr resulted in an increased capacity to forma biofilmin 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 Significance: The 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.

Original languageEnglish (US)
Article numbere10790
JournalPloS one
Volume5
Issue number5
DOIs
StatePublished - Sep 17 2010

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Accessories
Biofilms
Regulator Genes
regulator genes
biofilm
Staphylococcus aureus
Genes
mutation
Mutation
nucleases
mutants
Peptide Hydrolases
proteinases
functional status
proteinase inhibitors
Protease Inhibitors
antibiotics
Anti-Bacterial Agents
Phenotype
phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Beenken, K. E., Mrak, L. N., Griffin, L. M., Zielinska, A. K., Shaw, L. N., Rice, K. C., ... Smeltzer, M. S. (2010). Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation. PloS one, 5(5), [e10790]. https://doi.org/10.1371/journal.pone.0010790

Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation. / Beenken, Karen E.; Mrak, Lara N.; Griffin, Linda M.; Zielinska, Agnieszka K.; Shaw, Lindsey N.; Rice, Kelly C.; Horswill, Alexander R.; Bayles, Kenneth W; Smeltzer, Mark S.

In: PloS one, Vol. 5, No. 5, e10790, 17.09.2010.

Research output: Contribution to journalArticle

Beenken, KE, Mrak, LN, Griffin, LM, Zielinska, AK, Shaw, LN, Rice, KC, Horswill, AR, Bayles, KW & Smeltzer, MS 2010, 'Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation', PloS one, vol. 5, no. 5, e10790. https://doi.org/10.1371/journal.pone.0010790
Beenken KE, Mrak LN, Griffin LM, Zielinska AK, Shaw LN, Rice KC et al. Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation. PloS one. 2010 Sep 17;5(5). e10790. https://doi.org/10.1371/journal.pone.0010790
Beenken, Karen E. ; Mrak, Lara N. ; Griffin, Linda M. ; Zielinska, Agnieszka K. ; Shaw, Lindsey N. ; Rice, Kelly C. ; Horswill, Alexander R. ; Bayles, Kenneth W ; Smeltzer, Mark S. / Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation. In: PloS one. 2010 ; Vol. 5, No. 5.
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