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Title: The role of the general stress response in staphylococcal survival during exposure to host immune defences and antibiotics
Author: Ranganathan, Nishanthy
ISNI:       0000 0004 9356 9756
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Persistent staphylococcal bacteraemia remains an important and frequent cause of morbidity and mortality, despite the availability of apparently effective antimicrobial therapy. Antibiotic tolerance is poorly characterised since despite bacteria being able able to survive prolonged antibiotic exposure without the acquisition of resistance mutations, they are found to be sensitive to antibiotics in vitro. SigB is a global regulator involved in the response of staphylococcal bacteria against acid, heat, salt and alcohol stresses. The majority of evidence for SigB in modulating antibiotic tolerance is from work from B. subtilis, MRSA or animal models. Through the construction of strains with controllable SigB activity and effector expression via an inducible promoter, the contribution of this stress response system to survival of S. aureus was investigated in a model that built in its complexity; (a) antibiotic susceptibility using a standard bacterial killing assay, (b) immune system susceptibility using an ex vivo whole blood model and then (c) a combination of the two stresses in one model. Results revealed that the SigB stress response system promoted bacterial survival during exposure to both antibiotics and host immune cells. Subsequent work identified two genes through which SigB exerts at least some of its protective effects in an antibiotic specific manner. The work described in this thesis is the first to demonstrate involvement of SigB in modulating staphylococcal survival during human host infection. The finding that that the loss of SigB sensitises bacteria to killing by both antibiotics and the immune system, makes SigB an attractive therapeutic target to increase the rate of bacterial eradication during chronic infection. Future work will determine the molecular mechanism by which SigB promotes phenotypic drug tolerance and use this information to develop new therapeutic approaches to enhance the efficacy of existing antibiotics.
Supervisor: Edwards, Andrew ; Sriskandan, Shiranee Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral