Tuberculosis Drug Discovery
The ITR is pursuing several strategies for discovery of new anti-TB agents. This includes large scale screening of both natural and synthetic compounds for those that demonstrate specificity of activity (i.e. inhibit the TB bacillus but not mammalian cells). Lead compounds are then optimized by synthesis or semi-synthesis. In addition we are attempting to optimize the anti-TB activity of classes of antibiotics used for other infections but that have not been clinically active in tuberculosis. Activity of all lead compounds are assessed in vitro and in vivo. Ultimately clinical trials will be conducted with collaborators in TB-endemic regions.
New Tools Development
Screening assay development
M. tuberculosis grows very slowly, requiring 18 days to form mature colonies on agar-based media. Indirect determinations of viability (and thus drug activity) can be completed in a less than a week by measuring some aspect of metabolism. Microplate-based metabolic or gene reporter assays make possible the testing of thousands of substances in a short period of time and facilitates the use of robotics. Improving the sensitivity of these assays allows the possibility of using them in the more advanced analyses where TB is growing in macrophage cell culture or in the lungs of mice. Of even greater importance is the development of gene reporters that will work in dormant TB. This would greatly facilitate the search for drugs that might shorten the treatment duration of clinical tuberculosis.
Clinical assay development - detecting drug resistance in resource-poor settings
Tests that are both inexpensive and rapid are needed to make possible the detection of drug-resistant TB in developing countries. ITR scientists have collaborated in the development of prototypes that are being evaluated clinically in several countries. Further refinements are currently being developed.