This proposal aims to evaluate the efficacy of Native American ethnobotanical treatments for tuberculosis for the purpose of making available acceptable, affordable alternatives to current TB drugs, especially in developing countries with massive TB case loads such as the People's Republic of China. No new drugs have been introduced for the treatment of tuberculosis for the past 30 years. Today the world faces a resurgence of tuberculosis, the number one bacterial killer and an intensive search has been launched to find new drugs, primarily in the public, academic and biotech sectors. One of the confounding factors is the high cost of any new drug development (and thus cost of the drugs to the public) together with the relatively low profit potential for TB drugs, thus discouraging big pharmaceuticals from investing in TB. Native Americans relied entirely upon botanical treatments for tuberculosis following the epidemics that occurred with the introduction of this disease by the European colonialists. Some of these treatments continued to be used ethnomedically throughout the 20th century. Preliminary phytochemical and bacteriological studies confirmed the anti-TB activity of 2 such plants but studies were discontinued prematurely due to lack of funds (and perceived lack of urgency at the time). This study will evaluate the activity of ethobotanical and organic solvent preparations of 2 plants in mice infected by aerosol with low doses of Mycobacterium tuberculosis. Both acute and chronically infected mice will be treated for 2-3 weeks and the treatment evaluated by determining the number of bacteria in lungs and comparing to untreated controls. Concurrent with this evaluation will be a bioassay-guided fractionation of the plants in order to identify the active principle(s) for the purpose of standardization of botanical preparations. At every step of the fractionation, both cytotoxicity and anti-TB activity will be assessed in an attempt to identify a preparation requiring minimal processing that possesses maximum selectivity for the tubercle bacillus. Such a preparation would be the subject of further development for use in clinical TB
