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The MM4TB Project

The More Medicines for Tuberculosis (MM4TB) consortium evolved from the highly successful FP6 project, New Medicines for TB (NM4TB), that delivered a candidate drug for clinical development two years ahead of schedule. Building on these firm foundations and exploiting its proprietary pharmacophores, MM4TB will continue to develop new drugs for TB treatment.



In this video, Prof. Stewart Cole, Coordinator of MM4TB and chair of the Global Health Institute at the EPFL, describes a new drug candidate and how it kills Tuberculosis bacteria.


Tuberculosis

Chest X ray
Chest X-ray of a person with advanced tuberculosis. The black area shows the diseased tissue
Tuberculosis (TB) is one of the oldest diseases known to man. There is evidence from Egyptian mummies that it was present before 4000 BC and Hippocrates gave the first clear description. TB ravaged much of Europe in the middle ages and in the 19th Century killed one person in seven, which led Sir William Osler to remark that "Every man has a little tuberculosis". It was only in 1882 that Koch first described the TB bacillus, Mycobacterium tuberculosis (M. tb), as the infectious agent. Today the statistics are staggering and would shock mankind if they were widely known: one third of the world's population is infected with TB; one person is infected every second; someone dies from the disease every 15 seconds; 30 million people will die from TB over the next decade; TB kills more adults than AIDS, malaria and all other tropical diseases combined.

TB is no respecter of geographical or political boundaries and is found in every country; it transcends social class and wealth and is not simply a disease of poverty, although the poorest people are likely to suffer more visibly from it. The increasing incidence of AIDS has given rise to greater numbers of TB infections and deaths and has thwarted the drive to eradicate the disease. As a consequence of AIDS, there is now a higher incidence of TB in many African countries than there was 20 years ago when treatment regimens were beginning to lessen the disease.

TB in AIDS is also an issue because it can show atypical symptoms and so is poorly diagnosed. As a consequence, inadequate treatment is given that can increase the incidence of multi-drug resistant disease and so make the situation dangerously worse. Finally, there is also a serious problem in treatment of TB in AIDS patients because the drugs used, particularly rifampicin, cause induction of hepatic CYP enzymes that facilitate metabolism of some AIDS drugs and so render them ineffective. Thus, a new agent to treat TB that lacks this property would offer major advantages. The increasing occurrence of multiple-drug resistant disease (MDR-TB) even in developed countries, and particularly in Eastern Europe, threatens the possibility of a major epidemic of TB across Europe as a whole.

TB vaccines are widely used in Europe and elsewhere and seem to offer some protection from the disease but have proved a dismal failure in developing countries, like India and in Africa, where the disease is endemic. There is extensive work on new vaccine approaches being undertaken; some excellent work is also being supported by the EU. However, it seems likely that it will take two generations to reach widespread success, if indeed this can ever be achieved. Thus, there will be a continuing need for drugs to treat TB and particularly ones that are effective against currently virulent strains and mutations of these, particularly those that are already multi-drug resistant.

Research

An integrated approach will be implemented by a multidisciplinary team that combines some of Europe's leading academic TB researchers with two major pharmaceutical companies and four SMEs, all strongly committed to the discovery of anti-infective agents. MM4TB will use a tripartite screening strategy to discover new hits in libraries of natural products and synthetic compounds, while concentrating on both classical and innovative targets that have been pharmacologically validated. Whole cell screens will be conducted against Mycobacterium tuberculosis using in vitro and ex vivo models for active growth, latency and intracellular infection. Hits that are positive in two or more of these models will then be used for target identification using functional genomics technologies including whole genome sequencing and genetic complementation of resistant mutants, yeast three hybrid, click chemistry and proteomics. Targets thus selected will enter assay development, structure determination, fragment-based and rational drug design programs; functionally related targets will be found using metabolic pathway reconstruction. Innovative techniques, based on microfluidics and array platforms, will be used for hit ranking, determining rates of cidality and confirming mechanism of action. Medicinal chemistry will convert leads to molecules with drug-like properties for evaluation of efficacy in different animal models and late preclinical testing.

MM4TB will employ novel whole cell and phenotypic approaches for M. tb in conjunction with a prioritized list of validated targets, seeking to generate novel drug leads. A major objective of this initiative is to validate at least five new drug targets pharmacologically and discover at least one family of candidate drugs (CD). These CD can be transferred to biotechnology companies or pharmaceutical partners for further development. The involvement of two leading pharmaceutical companies in MM4TB is a major asset; in its previous form as NM4TB (New Medicines for Tuberculosis) the consortium successfully discovered the benzothiazinone (BTZ) series, now in late stage preclinical development.