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: α-hemolysin secretion and fibronectin binding in vitro. In addition, salicylic acid reduced the expression of the α-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 sigBrepressible 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.

Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: New role for the NADPH oxidase in host defense

“…We used an air pouch model of skin infection that mimics systemic staphylococcal infection in humans initiated as a cutaneous or s.c. abscess (31) and in which bacteremia and metastatic infection follow agr-dependent RNAIII production (7). We quantified quorum sensing in vivo by infecting with early exponential phase bacteria containing an RNAIII promoter-GFP construct and measuring induction of both the percentage of fluorescent bacteria and their magnitude of fluorescence over time (7,8,24).…”

“…AIP group I WT RN6390, its agr deleted mutant RN6911, and AIP group I methicillin-resistant S. aureus (MRSA) COL strains containing plasmids encoding the promoter for RNAIII or ␣ hemolysin (hla) driving expression of GFP were generated as described (24). Early exponential phase, nonfluorescent bacteria with a mean channel of fluorescence (MCF) of 10-20 by flow cytometry (FACSCalibur, Becton Dickinson) were prepared as described (7).…”

Infectious complications in patients with cardiac implantable electronic devices – risk factors, prevention and prognosis

“…8,9 Pacemaker lead loops were defined as the pres ence of excessively elongated leads in the atrium or in the ventricle protruding into the tricuspid valve orifice (FIGURE 1B and 1C). 10 Intracardiac lead abrasion (ILA) was diagnosed if damage to the outer lead insulation in the in tracardiac segment (15)(16)(17)(18)(19)(20) cm from the lead tip) was detected during visual inspection (FIGURE 1D and 1E). 10 Data analysis Potential risk factors for infec tious complications were analyzed in patients with CIED infections, who were divided into 2 main groups: with PI and with LRIE, and were further subdivided into those with IPI, ILRIE, and LRIE + PI, as compared with patients with non infectious complications.…”

Platelet-Bacterial Interactions in the Pathogenesis of Infective Endocarditis — Part I: The Streptococcus

“…Consistent with this, a recent study has examined the effect of antiplatelet drug Reopro (abciximab) in the treatment of sepsis in mice [113] and the use of cyclooxygenase inhibitors, e.g. aspirin and inbuprofen continue to be investigated [114][115][116][117]. Critically, future therapies must balance immune function and haemostatic function of platelets making thorough understanding of platelet-bacterial interactions and bacterial induced platelet activation essential for future drug development.…”