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Title: The challenge of drug resistant tuberculosis
Author: Satta, Giovanni
ISNI:       0000 0004 7660 0395
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Tuberculosis remains a major cause of morbidity and mortality globally with 10.4 million new cases worldwide in 2015 (WHO data). Drug resistance has also emerged as a public health concern in high-income countries as a result of immigration from endemic areas, the HIV pandemic and immunosuppressive treatments. The challenge this expansion poses to public health authorities is illustrated by an outbreak of isoniazid resistant tuberculosis in London (UK) in which over 400 cases have been diagnosed since 1995. The main scope of this thesis is to address the challenges of drug resistant tuberculosis, with a particular focus on the applications of whole genome sequencing to the drug discovery process. A multi-strategy approach has been adopted, starting with the use of next generation sequencing to understand pathogenicity and discover new potential drug targets, to the laboratory testing of new compounds. Using a sub-cluster of strains from the London outbreak, our findings have confirmed the utility of whole genome sequencing in understanding the pathogenesis of clinical strains, discovering specific genetic mutations that may have allowed the outbreak to persist for years. At the same time, we have also integrated sequencing technologies within the screening process of new compounds and we have demonstrated its potential role in elucidating the mechanism of action of old and new drugs, in particular para-aminosalicylic acid and its newly created analogues. The repurposing of current drugs (carbapenems) has been evaluated as a potential treatment in case of drug resistance whilst gold nanoparticles have been assessed as alternative compounds. Hence, this thesis has reflected the complexity of addressing the challenge of drug resistant tuberculosis and how a multi strategy approach is essential for the eradication of this global pathogen.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available