The challenge of drug resistant tuberculosis

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 ... (continues)