title: Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus.
abstract: Aspirin has been previously shown to reduce the in vivo virulence of Staphylococcus aureus in experimental endocarditis, through antiplatelet and antimicrobial mechanisms. In the present study, salicylic acid, the major in vivo metabolite of aspirin, mitigated two important virulence phenotypes in both clinical and laboratory S. aureus strains: alpha-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the alpha-hemolysin gene promoter, hla, and the fibronectin gene promoter, fnbA. Transcriptional analysis, fluorometry, and flow cytometry revealed evidence of salicylic acid-mediated activation of the stress-response gene sigB. Expression of the sigB-repressible global regulon sarA and the global regulon agr were also mitigated by salicylic acid, corresponding to the reduced expression of the hla and fnbA genes in vitro. Studies in experimental endocarditis confirmed the key roles of both sarA and sigB in mediating the antistaphylococcal effects of salicylic acid in vivo. Therefore, aspirin has the potential to be an adjuvant therapeutic agent against endovascular infections that result from S. aureus, by downmodulating key staphylococcal global regulons and structural genes in vivo, thus abrogating relevant virulence phenotypes.
authors.affiliation: Division of Infectious Disease, Harbor-UCLA (University of California-Los Angeles), Torrance, California, USA.
authors.forename: Leon Iri
authors.initials: LI
authors.lastname: Kupferwasser
authors.forename: Michael R
authors.initials: MR
authors.lastname: Yeaman
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
authors.forename: Deborah
authors.initials: D
authors.lastname: Kupferwasser
authors.forename: Yan-Qiong
authors.initials: YQ
authors.lastname: Xiong
authors.forename: Marco
authors.initials: M
authors.lastname: Palma
authors.forename: Ambrose L
authors.initials: AL
authors.lastname: Cheung
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004696:Endocarditis / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000378:metabolism / Q000382:microbiology*; D005340:Fibrinogen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D006460:Hemolysin Proteins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D008856:Microscopy, Fluorescence; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011817:Rabbits; D020156:Salicylic Acid / Q000494:pharmacology*; D012808:Sigma Factor / Q000378:metabolism; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D002352:Carrier Proteins; D005353:Fibronectins; D006460:Hemolysin Proteins; C492107:SarA protein, Staphylococcus aureus; C079011:SigB protein, Bacteria; D012808:Sigma Factor; C021091:staphylococcal alpha-toxin; D005340:Fibrinogen; D020156:Salicylic Acid