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

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.

Despite the existence of treatments for tuberculosis (TB), TB continues to present a major healthcare challenge, accounting for nearly 9 million new infections and over 1 million deaths p.a.; indeed, this global health threat is increasing given the increased susceptibility of HIV-infected individuals to TB, the limited efficacy of the BCG vaccine and most worryingly, the growing prevalence of drug-resistant strains of Mycobacterium tuberculosis, the microorganism causing the disease. Treating TB requires a drug cocktail that has to be taken for at least six months, extending to two years for infections caused by multi drug-resistant strains of M. tuberculosis. A largely successful campaign by the WHO to stem the rise of TB has not diminished the urgent need for better drugs, acting against new cellular targets, to alleviate the devastating impact of this disease. The principal aim of this MICA is to expand the pipeline of new targets for future TB drug-discovery programmes. In achieving this objective, we will also develop new tool compounds, which will allow us to gain detailed insight into the fundamental biology of M. tuberculosis. To this end, hits from GSK DDW's most recent high-throughput phenotypic screening campaigns will be prioritised according to their potency and favourable physicochemical properties for future development in hit-optimisation and lead-identification programmes. These hits will then be subjected to a combination of genetic, chemical proteomic, metabolomic and structural studies to first identify and then to validate their associated cellular targets and ultimately to determine their mode of action. The guiding principle of this multidisciplinary, academic-industrial initiative is to focus on high-quality, potent compounds hitting diverse targets to deliver the best possible starting points for future TB drug-discovery initiatives.

Impact on the Treatment of Disease: This MICA Research Grant will increase our knowledge of tuberculosis (TB) biology and Mycobacterium tuberculosis physiology, whilst delivering new TB drug targets and compounds for future drug-discovery studies. The most far-reaching impact of the work would therefore be the introduction of new drugs for treating TB. Reducing the high morbidity and mortality rates of this disease by introducing more efficacious drugs, which also target increasingly drug-resistant strains of M. tuberculosis, would have global impact upon the health and wellbeing of Society. Furthermore, since TB mostly affects young adults in their productive years, new TB drugs would also have significant economic impact, particularly in those developing countries where the disease is most prevalent. Introducing a new TB drug on to the market and realising its impact upon health and the global economy needs to be viewed on at least a 10-15-year timescale.

Who will benefit from this research: This research grant will provide excellent training opportunities in molecular synthesis and mode-of-action studies. The requested UoB Post-Doctoral Research Associates (PDRAs), Dr Abrahams and Dr Cabanillas, and the PDRA (to be named) at the Crick will work in established and highly successful groups led by the PI and co-PIs. They will work closely with one another and other co-workers and take advantage of the valuable knowledge-transfer opportunities that this multidisciplinary project presents and which will be bolstered by secondments to our industrial Project Partner, GSK DDW. The project management (see the Heads of Terms Agreement) will ensure training needs are identified and addressed, skills are transferred, and opportunities and results exploited. By the end of the project, the PDRAs will be in demand from prospective employers requiring skilled researchers in advanced chemical synthesis and antimicrobial research.

How the researchers will benefit from this project: Career development. In addition to laboratory group meetings, regular meetings with the researchers will be used to set goals, trouble-shoot and review progress. This will keep the research activity focused and ensure that outputs are maximised and milestones achieved. Both UoB and the Crick offer mentoring schemes, which ensure that research and CPD training needs and career opportunities are identified efficiently and developed effectively. The PDRAs will further benefit from the specialist methodologies provided by our industrial Project Partner, which they will experience first hand through secondments at GSK DDW.

Other academic beneficiaries and commercial exploitation. The research outputs from this project will strengthen the PI's and Co-PIs' positions as international leaders in TB research whilst also impacting on the international scientific community, who will benefit from our improved understanding of mycobacterial biology and the disclosure of new TB drug targets. Both academic partner institutions have made significant recent investment to support research in the life sciences; this Research Grant will provide a valuable opportunity to build on these strong platforms and establish international centres of excellence for biomedical research that attract the best researchers from across the globe. The protection of IP and opportunities for commercial exploitation will be pursued through the Research and Technology Transfer Units based at UoB and the Crick.

The wider public. Whilst the public will benefit in the long term from the development of new TB drugs, over the duration of this project, the research team will engage the public in various ways (outreach activities, social media, internet) to disseminate its findings and highlight the importance of scientific research and the urgent need to develop new TB treatments and address the growing issue of antibiotic resistance.