Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants

Cook, Simon M., Skora, Amanda, Walker, Mark J., Sanderson-Smith, Martina L. and McArthur, Jason D. (2014) Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants. Biochemical Journal, 458 1: 23-31. doi:10.1042/BJ20131305


Author Cook, Simon M.
Skora, Amanda
Walker, Mark J.
Sanderson-Smith, Martina L.
McArthur, Jason D.
Title Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants
Journal name Biochemical Journal   Check publisher's open access policy
ISSN 0264-6021
1470-8728
Publication date 2014-02-15
Year available 2014
Sub-type Article (original research)
DOI 10.1042/BJ20131305
Open Access Status DOI
Volume 458
Issue 1
Start page 23
End page 31
Total pages 9
Place of publication London, United Kingdom
Publisher Portland Press
Language eng
Abstract In contrast to mild infections of Group A Streptococcus (GAS) invasive infections of GAS still pose a serious health hazard: GAS disseminates from sterile sites into the blood stream or deep tissues and causes sepsis or necrotizing fasciitis. In this case antibiotics do not provide an effective cure as the bacteria are capable to hide from them very quickly. Therefore, new remedies are urgently needed. Starting from a myxobacterial natural products screening campaign, we identified two fatty acids isolated from myxobacteria, linoleic and palmitoleic acid, specifically blocking streptokinase-mediated activation of plasminogen and thereby preventing streptococci from hijacking the host's plasminogen/plasmin system. This activity is not inherited by other fatty acids such as oleic acid and is not attributable to the killing of streptococci. Moreover, both fatty acids are superior in their inhibitory properties compared to two clinically used drugs (tranexamic or ε-amino caproic acid) as they show 500-1000 fold lower IC50 values. Using a humanized plasminogen mouse model mimicking the clinical situation of a local GAS infection that becomes systemic, we demonstrate that these fatty acids ameliorate invasive GAS infection significantly. Consequently, linoleic and palmitoleic acid are possible new options to combat GAS invasive diseases.
Formatted abstract
SK (streptokinase) is a secreted plasminogen activator and virulence factor of GAS (group A Streptococcus). Among GAS isolates, SK gene sequences are polymorphic and are grouped into two sequence clusters (cluster type-1 and cluster type-2) with cluster type-2 being further classified into subclusters (type-2a and type-2b). In the present study, we examined the role of bacterial and host-derived cofactors in SK-mediated plasminogen activation. All SK variants, apart from type-2b, can form an activator complex with Glu-Plg (Glu-plasminogen). Specific ligand-binding-induced conformational changes in Glu-Plg mediated by fibrinogen, PAM (plasminogen-binding group A streptococcal M protein), fibrinogen fragment D or fibrin, were required for type-2b SK to form a functional activator complex with Glu-Plg. In contrast with type-1 and type-2a SK, type-2b SK activator complexes were inhibited by α2-antiplasmin unless bound to fibrin or to the GAS cell-surface via PAMin combination with fibrinogen. Taken together, these data suggest that type-2b SK plasminogen activation may be restricted to specific microenvironments within the host such as fibrin deposits or the bacterial cell surface through the action of α2-antiplasmin. We conclude that phenotypic SK variation functionally underpins a pathogenic mechanismwhereby SK variants differentially focus plasminogen activation, leading to specific niche adaption within the host.
Keyword Fibrinogen
Plasminogen
Streptococcus pyogenes
Streptokinase
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID VH-GS-202
55880102
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
 
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