In bringing together a number of research scientists with expertise in a range of disciplines, an outcome, beyond that which any individual group could achieve, can be envisaged. The consortium is convinced to build a very efficient pipeline from molecular biology and bench chemistry to in vivo evaluation. These efforts are expected to yield different inhibitors targeting novel targets. Such drugs should not only attack novel targets, they should also shorten the time of treatment, the driving force for the emergence of drug-resistant tuberculosis.
Validation and characterization of targets
Genetically it will be demonstrated that the targets selected are essential for either the growth or pathogenesis of M. tuberculosis where this has not already been shown. For selected targets, strains of M. tuberculosis in which the concentration of the target can be varied, will be produced. Additionally, recombinant proteins of the targets will be produced, permitting biochemical characterization where appropriate, as well as the development of suitable assays for screening of inhibitors synthesized
Interaction with the host cellular machinery
Chemical compounds inhibiting the Mycobacterium replication cycle or activating the killing potential of host cellular machinery in cell-based assays will be identified and characterized.
Design and synthesis of new enzyme inhibitors as potential Mycobacterium tuberculosis drugs
Chemical synthesis of new antimycobacterial agents that will have a novel mode of action to overcome the problem of resistance and allow cost-effective and efficient treatment will be developed and exploited. Focussing on several target enzymes (FAAL, PKS, F1F0-ATP synthase, thymidylate synthase (ThyX), DNA helicase (UvrD)), several medicinal chemistry programs will be installed yielding new, potent enzyme inhibitors.
Identification of novel drugs against Mycobacterium tuberculosis in vivo
A pipeline for a continuous feed-in of pretested compounds of potential anti-tuberculosis activity to screen and consecutively select, starting from broth culture assays (<100 candidates), via macrophage and lung parenchyma cell assays (<50 drug candidates), to mouse aerosol infection models (<10 candidates) will be established.
The multidisciplinary approach combining structure analyses, chemistry, cell biology, and microbiology will provide novel insights into the mechanisms which M. tuberculosis employs for its persistence in the host. Hence, findings generated in this consortium will also provide valuable information for the design of novel antibiotics beyond this disease.
This consortium reflects awareness of the need for new drugs to treat TB by bringing together experts of different disciplines from Europe and India to generate an activity that will lead to the identification of novel drugs, including drugs directed at dormant TB and drugs that interfere with host–pathogen interactions. Hence, this research project comprises innovative strategies towards control of a major health problem of global dimension.