Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.689111
Title: Mechanistic studies on Zymogen-Activator and Adhesion Proteins (ZAAPs) as thrombolytic drugs and bacterial virulence factors
Author: Huish, Sian
ISNI:       0000 0004 5917 6238
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Abstract:
Streptokinase (SK), expressed by Lancefield Group A, C and G β-haemolytic Streptococci and Staphylocoagulase (SCG), expressed by S. aureus, are bacterial virulence factors which belong to a family of proteins known as Zymogen-activator and adhesion proteins (ZAAPs). SK and SCG are responsible for the non-proteolytic activation of plasminogen and prothrombin, respectively. Understanding of SK activity is exclusively based on the Group C (GCS) S. equisimilis H46a SK, a 'clot buster' or thrombolytic used in the treatment of Myocardial Infarction (MI), which exhibits no fibrin specificity. SK is the most used thrombolytic worldwide. Here, detailed kinetic studies in purified assay systems explored the mechanistic variation between a recombinant H46a SK (rSK H46a) and a Group A Streptococcal SK (M1GAS), most typically isolated in invasive human infection. This work demonstrates a fibrin specific mechanism for M1GAS SK and proposes a kinetic model for M1GAS SK plasminogen activation, to compliment the 'Trigger and Bullet' hypothesis for H46a SK by Bock and colleagues. This work has relevance to the use of SK variants, with enhanced fibrin specificity, for improvement of thrombolytic therapies. Cardiovascular diseases such as myocardial infaraction and ischaemic stroke are significant casues of mortality, particularly in the developing world. Access to Alteplase, an expensive recombinant tPA and the only licensed treatment for stroke, is limited and there is interest in the use of SK for this purpose. Furthermore, microbial resistance is an increasing health burden, as demonstrated by programs such as the Longitude prize. Exploring the mechanisms of bacterial virulence factors at the molecular level such as this could provide rationale for the development of much-needed new antimicrobial technologies.
Supervisor: Fairweather, Neil Sponsor: National Institute for Biological Standards and Control
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.689111  DOI: Not available
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