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New drugs for persistent tuberculosis: Exploitation of 3-D structure of novel targets, lead optimisation and functional in-vivo evaluation

Final Report Summary - NEWTBDRUGS (New drugs for persistent tuberculosis: Exploitation of 3-D structure of novel targets, lead optimisation and functional in-vivo evaluation)

Tuberculosis (TB) is one of the most deadly infectious diseases in the world. The key problem arising in TB treatment is the six to eight months long treatment duration which very often leads to non-compliance. Patients frequently get better quickly on an intense course of antibiotic chemotherapy, and therefore stop taking the drugs before the infection is eliminated. The high rates of patient non-compliance lead to more deaths, as well as, to the creation of chronic, infectious, drug-resistant TB strains, against which almost all existing antibiotics are ineffective or prohibitively toxic. Mycobacterium tuberculosis (MTB) has become a major health problem not only in developing but also in neighbouring countries of the European Community. In the face of the HIV / AIDS epidemic, new 'sterilising' drugs with shorter regimens are needed which would significantly increase patient compliance, substantially reduce the rate of emergence of antibiotic resistance, materially decrease the costs of treatment and shall prevent progression from latent infection to active disease.

New strategies are urgently needed for combating the problems of TB treatment. NEWTBDRUGS have made four scientific breakthroughs, which indicate that it is feasible to develop such a drug:
1. As part of a post-genomic, interdisciplinary research project supported by the EC, we have recently solved the three-dimensional (3-D) structure of several, persistence related drug targets of MTB. NEWTBDRUGS have obtained information on ligands for these targets.
2. Their work has shown that persistent MTB is metabolically active, and so it should be susceptible to specific chemotherapy, albeit different from current antibiotics.
3. New assays have been developed which have been used for screening drugs, which kill persistent MTB. These assays can distinguish between drugs such as Isoniazid, which have little action against persisters, and compounds, which are known to have some anti-persister activity such as pyrazinamide.
4. They have identified unique compounds, which kill MTB including Rifampicin resistant strains.

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