The Genomics of Multidrug-Resistant Tuberculosis Transmission (360G-Wellcome-201470_Z_16_Z)

An estimated 37 million lives were saved by tuberculosis treatment between 2000 and 2013. However, multidrug-resistant tuberculosis threatens this treatment success, costs 10 times more to treat and requires toxic antibiotics. The Mycobacterium tuberculosis genome is more variable than previously thought. This variability may explain differences in drug-resistance acquisition, bacterial fitness and transmission between lineages. Identifying which bacteria are most likely to survive, spread and acquire drug-resistance could allow expanded antibiotic therapy and contact tracing to be tailored to the bacterial genome. Preliminary analysis of 470 multidrug-resistant tuberculosis genomes in collaboration with world leading tuberculosis geneticists has demonstrated that multidrug-resistant tuberculosis strains independently evolve mutations in cell surface immunogenic proteins. Our hypothesis based on these findings is that these mutations improve bacterial fitness and facilitate multidrug-resistant tuberculosis spread. Genome sequencing two unique high-coverage cross-sectional Mycobacterium tuberculosis DNA collections, with metadata and epidemiological links, assembled during the candidate’s Wellcome Trust Fellowship in 2009 and 2013 will address these key questions: 1) What is the Mycobacterium tuberculosis sub-lineage association with drug resistance acquisition? 2) How is multidrug-resistant tuberculosis adaptively evolving to overcome the fitness cost of drug resistance? 3) Which adaptive mutations are expanding most rapidly in the population over time?