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New Antimycobacterials


Tuberculosis

Inhibitors of the Nonmevalonate Pathway of Isoprenoid Biosynthesis as Drugs Against Tuberculosis
Framework programme:
5
Project number:
QLK2-CT-2002-00887
EC contribution:
€ 1 500 000
Duration:
36 months
Type:
RS
Starting date:
1 September 2002

Keywords: Crystal structure; 1-deoxy-D-xylulose 5-phosphate; DOXP; drug design; isoprenoid; MEP; 2-C-methyl-D-erythritol-4-phosphate; Mycobacterium tuberculosis; reductoisomerase

Summary:

A new drug against tuberculosis (TB) will be developed, based on the inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) pathway. The DOXP pathway supplies M. tuberculosis with essential isoprenoids. In mammals, the DOXP pathway is absent and isoprenoids are synthesised by the mevalonate pathway. This means inhibitors of the DOXP pathway are non-toxic for the human host. Inhibitors of DOXP reductoisomerase (DXR), a key enzyme of the DOXP pathway, are to be developed as potential anti-TB drugs. In addition, the crystal structure of the mycobacterial GcpE enzyme will be solved to provide the basis for further drug development.

Problem:

Tuberculosis is a highly contagious infectious disease of humans caused by the bacterium Mycobacterium tuberculosis, and easily spread by airborne transmission. To date, about 2 to 3 million people worldwide succumb to the disease each year, and there are some 8 million new TB cases per year, over a quarter of a million of which occur in Eastern Europe. There is an urgent need for new, safe and efficient anti-TB drugs because with multidrug-resistant pathogens, the course of treatment increases from the normal six months to 18-24 months, and cure rates drop from nearly 100 % to less than 60 %.

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