MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery

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Mycobacterium tuberculosis, the microorganism causing tuberculosis (TB), is perhaps the single most important pathogen affecting mankind. Finding new antibiotics to cure TB is therefore one of the most pressing and exciting challenges in contemporary microbiology. Predominantly a disease of poverty, TB affects young adults in their productive years and hence also carries a large economic burden. Numbers published by the WHO are bleak: in 2015, approximately 9-10 million new cases of TB were reported and over 1 million people died from the disease. TB may be prevalent in the developing world but is also resurfacing in wealthy countries, with some 5,758 cases reported in 2015 in the UK alone. And yet, there is reason for cautious optimism. TB can be cured, albeit with a cocktail of drugs that need to be taken for at least six months. Moreover, new compounds, selected specifically for their ability to overcome the growing list of M. tuberculosis strains that are resistant to established drugs, are beginning to populate a small pipeline of potential future drugs. Indeed, in late 2012 and after a nearly 50-year hiatus, the FDA approved a new TB drug for clinical use. Still, the challenges of antibiotic discovery and development of drugs for treating TB remain formidable as M. tuberculosis is well shielded against most antibiotics by its unique cell-wall architecture. Such challenges are best met by combining expertise from the academic and pharmaceutical sectors, as this will ensure the development of new treatments is founded on a detailed knowledge of the biology of the bacterium. The principal aim of the proposed academic-industrial collaboration is to discover and validate new targets, which will provide the bedrock of future global TB drug-discovery activities. Using high-throughput screening of compound libraries, our industrial partners have identified a number of small molecules (so-called 'hits'), which kill M. tuberculosis. Working with our industrial partner, we have already amassed a considerable body of preliminary data. Combining traditional genetic and cutting-edge analytical tools, we have identified the cellular targets for some of these hits, some of which have been fed into the pipeline of activities that sees an initial hit developed into a drug. Significantly, in determining the mode of action for one of these new inhibitors we were also able to uncover novel features of lipid metabolism in mycobacteria. A number of very promising hits have now emerged from two new screening campaigns. These are primed for development and have been ranked by our industrial partners based on i) their potency and ii) key physicochemical properties, which predict their potential for successful drug development. These prioritised hits will be transferred to Birmingham and the Crick where we will use our expertise to identify the mycobacterial proteins that these molecules act upon and then elucidate how these compounds kill bacilli, i.e. their mode of action. From these studies we will discover novel fundamental biology of M. tuberculosis. We will also find out where this organism is particularly vulnerable, which will be vital for directing future TB drug-discovery activities. Drug discovery is highly multidisciplinary. The proposed collaboration and rich body of preliminary data present a compelling opportunity to unite basic and applied science and turn this into knowledge that can be used to treat a debilitating disease which represents one of the most pressing healthcare challenges for society in the 21st Century.