Nanoparticle based rapid diagnostics for TB disease Tuberculosis (TB) caused by the Mycobacterium tuberculosis (M. tb) bacterium is one the three major causes of infectious disease deaths worldwide. Approximately one quarter of the global population is infected, with annually 10 million new cases and 1.4 million deaths. While TB is treatable with suitable antibiotic combinations, disease symptoms are variable and easily confused with other conditions, meaning that individuals with active disease and capable of infecting others are not always quickly identified, allowing continued transmission. Fast, accurate identification of these patients is key to achieving the prompt antibiotic administration necessary to prevent infected individuals spreading disease. The World Health Organisation (WHO) has identified new diagnostic technologies to detect TB disease as one research focus for their End TB Strategy designed to reduce TB incidence by 80 % by 2030. This proposal aims to develop and evaluate tools to capture and detect M. tb in samples from patients with possible TB disease: specifically sputum coughed up by infected adults. The long term goal is to create a rapid diagnostic method capable of identifying TB disease and that is able to be used in resource-poor settings (i.e. the low and middle-income countries where the TB disease burden is greatest and medical infrastructure is limited). Our method combines three complementary technologies to capture and identify M. tb: 1. generation of specific sugar molecules able to bind selectively and tightly to the M. tb cell; and their attachment to 2. magnetic and 3. fluorescent particles. This will create two types of material able to bind M. tb - a magnetic particle, making the bacterium magnetic and enabling its capture in a magnetic field; and a fluorescent particle making the bacterium fluorescent and able to be detected using a microscope. Combining these particles will enable us to capture, concentrate and visualise M. tb from patient samples. Our experimental approach divides into three workpackages (WPs): WP1 focuses on using a range of innovative approaches to synthesise sugars able to bind M. tb; WP2 focuses on attaching these sugars to magnetic and fluorescent particles and investigating the physical properties (size, shape, magnetic and optical characteristics) of the resulting materials; and WP3 on evaluating the binding of these materials to bacteria. We will first test binding to the weakened BCG (vaccine) strain of M. tb in laboratory media mimicking the composition of sputum, comparing this with binding to other bacteria that may be present in these samples to establish their selectivity for M. tb over other species. We will extend these experiments to study M. tb strains isolated from patients. Finally we will evaluate our method on samples from patients presenting with possible TB infection, comparing our results with parallel tests carried out on the same samples using traditional methods (growth in culture, sputum microscopy or the GeneXpert system that detects M. tb genetic material). The results will determine whether this new approach can detect bacteria in the quantities present in patient samples and is able to discriminate between M. tb and other bacteria. Workpackages 1 and 2 will take place at the University of Bristol (UoB), workpackage 3 at UoB and the Kenya Medical Research Institute (KEMRI) where all experiments with patient-derived bacteria and samples will take place. Kenya is a WHO High Burden TB country; KEMRI has the expertise and infrastructure necessary to evaluate TB detection methods. Our proposal combines novel science (development of new materials that selectively bind M. tb) with support for posts, infrastructure and bidirectional exchange visits that will develop research capacity in Kenya.  The diversity of our research team and the strong links between KEMRI, healthcare practitioners and policymakers will ensure delivery of impact in both the research community and potential end users. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.