Final Report Summary - 02-SENSITIVE TARGETS (Oxygen-sensitive enzymes of the mevalonate-independent isoprenoid biosynthesis pathway as targets for new antimalarial and anti-TB drugs)
In plasmodium and mycobacterium, isoprenoids are synthesised by the mevalonate-independent 1-deoxy-D-xylulose 5-phosphate (DOXP) pathway which is absent in humans. The last two steps of the DOXP pathway are mediated by enzymes, which contain oxygen-sensitive iron-sulphur clusters and catalyse unique radical-type reactions. Using an advanced high resolution screening technology the project aimed at the identification of lead inhibitors to be developed as novel drugs against malaria and tuberculosis.
Isoprenoids are essential for all organisms. In humans, isoprenoids are synthesised via the well-established mevalonate pathway. In most bacteria and some protozoal parasites, as well as in the plastids of plants, a completely unrelated biosynthetic route, the DOXP pathway, is used. Work on the DOXP pathway represents a relatively young field of research. In particular, any attempts to demonstrate the catalytic activity of some enzymes involved failed until very recently. This was mainly due to the fact that these enzymes are highly sensitive to oxygen.
Since it is absent in humans, the DOXP pathway provides an attractive new drug target for the treatment of tuberculosis and malaria. It has already been shown in four clinical trials that fosmidomycin, an inhibitor of the DOXP pathway, is active against malaria. Therefore, the project aimed at the development of inhibitors of additional targets within the DOXP pathway. As a long-term goal, the development of a synergistic drug combination inhibiting two enzymes of the DOXP pathway simultaneously was envisaged.
The project will be continued with the short term goal to elucidate the chemical structures of the active compounds present in the identified natural product extracts. These compounds will be developed through additional medicinal chemistry work into drug candidates. In the longer term, the development of synergistic drug combination inhibiting two enzymes of the DOXP pathway simultaneously is envisaged. The drugs finally expected to emerge from the project will be of particular value for the treatment of infections with pathogens resistant to conventional drugs and provide the potential to become a new mainstay in anti-TB and anti-malarial therapy.
Isoprenoids are essential for all organisms. In humans, isoprenoids are synthesised via the well-established mevalonate pathway. In most bacteria and some protozoal parasites, as well as in the plastids of plants, a completely unrelated biosynthetic route, the DOXP pathway, is used. Work on the DOXP pathway represents a relatively young field of research. In particular, any attempts to demonstrate the catalytic activity of some enzymes involved failed until very recently. This was mainly due to the fact that these enzymes are highly sensitive to oxygen.
Since it is absent in humans, the DOXP pathway provides an attractive new drug target for the treatment of tuberculosis and malaria. It has already been shown in four clinical trials that fosmidomycin, an inhibitor of the DOXP pathway, is active against malaria. Therefore, the project aimed at the development of inhibitors of additional targets within the DOXP pathway. As a long-term goal, the development of a synergistic drug combination inhibiting two enzymes of the DOXP pathway simultaneously was envisaged.
The project will be continued with the short term goal to elucidate the chemical structures of the active compounds present in the identified natural product extracts. These compounds will be developed through additional medicinal chemistry work into drug candidates. In the longer term, the development of synergistic drug combination inhibiting two enzymes of the DOXP pathway simultaneously is envisaged. The drugs finally expected to emerge from the project will be of particular value for the treatment of infections with pathogens resistant to conventional drugs and provide the potential to become a new mainstay in anti-TB and anti-malarial therapy.
