Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus.

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.

In vitro susceptibility to thrombin-induced platelet microbicidal protein is associated with reduced disease progression and complication rates in experimental Staphylococcus aureus endocarditis: microbiological, histopathologic, and echocardiographic analyses.

BACKGROUND: Mammalian platelets contain small, cationic, staphylocidal peptides, termed thrombin-induced platelet-microbicidal proteins (tPMPs). Evidence suggests that tPMPs play a key role in host defense against endovascular infections, such as infective endocarditis (IE). In the present study, we evaluated the influence of differences in staphylococcal tPMP-susceptibility profiles in vitro on disease severity in experimental IE. METHODS AND RESULTS: Experimental IE was induced in rabbits with either a tPMP-susceptible or an isogenic tPMP-resistant Staphylococcus aureus strain. Vegetation size, left ventricular fractional shortening, and onset of aortic valvular regurgitation were serially assessed by echocardiography over an 11-day postinfection period. In addition, blood cultures were performed daily. Parameters delineated at autopsy included vegetation weights; bacterial densities in vegetations, myocardium, and kidneys; extent of valvular and perivalvular tissue damage; and renal embolization. The following significant differences were observed in animals infected with the tPMP-susceptible versus the tPMP-resistant S aureus strain: substantially lower bacteremia rates (P=0.02); reduced vegetation growth (P<0.001) and weight (P<0.001); a later onset of aortic valvular regurgitation (P=0.0039); increased preservation of left ventricular function (P<0.001); reduced valvular tissue damage (P=0.01) and perivalvular inflammation (P=0.015); and reduced bacterial densities in vegetations (P<0.001) and kidneys (P<0.01). CONCLUSIONS: The in vitro tPMP-susceptibility profile in S aureus substantially affects a number of well-defined cardiac and microbiological parameters related to disease severity and prognosis in IE. These findings underscore the likelihood that platelets mitigate the pathogenesis of endovascular infections via local secretion of antimicrobial peptides.