Preventing Staphylococcus aureus Sepsis through the Inhibition of Its Agglutination in Blood

Abstract

Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. When suspended in human or animal plasma, staphylococci are known to agglutinate, however the bacterial factors responsible for agglutination and their possible contribution to disease pathogenesis have not yet been revealed. Using a mouse model for S. aureus sepsis, we report here that staphylococcal agglutination in blood was associated with a lethal outcome of this disease. Three secreted products of staphylococci - coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA) – were required for agglutination. Coa and vWbp activate prothrombin to cleave fibrinogen, whereas ClfA allowed staphylococci to associate with the resulting fibrin cables. All three virulence genes promoted the formation of thromboembolic lesions in heart tissues. S. aureus agglutination could be disrupted and the lethal outcome of sepsis could be prevented by combining dabigatran-etexilate treatment, which blocked Coa and vWbp activity, with antibodies specific for ClfA. Together these results suggest that the combined administration of direct thrombin inhibitors and ClfA-antibodies that block S. aureus agglutination with fibrin may be useful for the prevention of staphylococcal sepsis in humans.

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

“…Similarly, treatment with compound 6e reduced staphylococcal association with fibrinogen (Fig. 3E), a key mechanism for the pathogenesis of bloodstream infections (13). We noticed a slight reduction in the abundance of Sbi (staphylococcal binder of Ig), a secreted protein that is not cleaved by SrtA, both in the ΔsrtA mutant and in staphylococci that had been treated with compound 6e (Fig.…”

“…inoculation of the pathogen (12,13). Earlier work used in vitro (inhibition of fluorogenic substrate cleavage) and virtual screening of compound libraries to identify sortase inhibitors (15,(52)(53)(54)(55)(56).…”

“…Genome sequencing revealed that all S. aureus isolates encode 17-21 surface proteins with LPXTG sorting signals, which fulfill diverse functions during the infectious process (11). SrtA mutants cannot assemble surface proteins into their envelope and are unable to form abscess lesions in organ tissues or cause lethal bacteremia when inoculated into the bloodstream of mice (12,13). In contrast, mutations that abrogate the expression of secreted virulence factors may cause attenuation but do not abrogate the ability of S. aureus to cause infectious diseases (12).…”

Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria

“…To evaluate the therapeutic efficacy of compound 1771, we used a mouse model of staphylococcal sepsis (23). Animals received i.p.…”

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

“…MRSA interactions with Fg are critical in pathogenesis (28)(29)(30)(31)(32)(33). For example, MRSA-Fg interactions, which result in bacterial agglutination, have been shown to contribute to pathogenesis by providing a microenvironment permissive for activation of the agrquorum sensing system (34).…”