A search for novel chemotherapy against tuberculosis amongst natural products

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Abstract
Novel screens have been developed for the detection of antitubercular activity among natural product extracts and these were compared with existing methodologies. Using bioassay- directed methods these screens have been employed to isolate novel antitubercular natural products from higher plant extracts and their structures have been determined. In particularly promising cases, exemplified by tryptanthrin, an alkaloid from the Chinese herb Strobilanthes cusia, i.a., conventional and combinatorial/matrix synthesis methodologies allowed the construction of hundreds of analogs in an attempt to optimize the activity. Tryptanthrin and its analogs are potent against multiresistant tuberculosis strains, are non toxic and give promising blood and tissue levels after oral administration to mice. The more potent of these, PA-505 and PA-5 10, are two orders of mdgnitude more potent than tryptanhin itself and have been extensively evaluated in vivo but failed 'to cure infected mice. Nonetheless, the methodologies developed are promising for discovering novel natural products for evaluation against multiresistant tubercular and other bacterial infections. At the beginning of this century tuberculosis was a devastating infectious disease, known as "the white plague"(l). Mankind had no effective drugs to treat it so morbidity and mortality were high, especially among the poor. However, as the standard of living in wealthy nations trickled down to the urban poor and various preventive measures became widely practiced, the incidence of the disease fell. Better nutrition, less crowded living circumstances, pasteurization of milk, quarantine, use of sanitaria, prohibition of expectoration in public places, periods free from depression and war, and the like, all played a useful role. In the middle years of this century, a succession of effective antitubercular chemotherapeutic agents was discovered. The incidence of the disease continued to decrease until it largely faded from the public consciousness as a health hazard in industrialized nations. Consequently research on TB fell to a very low level in industry and academia alike. In recent years, this picture has changed significantly as many inner city neighborhoods deteriorate economically and populations almost everywhere continue to increase. The incidence of reported TB infections began to rise in the United States in the mid 1980s for the first time in this century. Homelessness, poor nutrition, crowded conditions, IV drug use, development of multiply drug resistant strains of bacteria, ease of international travel, and immune suppression due to AIDS and other causes are regarded as largely responsible (I). Perhaps more disturbingly, the mortality rate (about 50% in the preantibiotic era; falling to about 15% in the antibiotic era with conventional TB) has increased to about 40% in immunocompetent patients with multidrug resistant TB (MDR-TB) and to 80% with MDR-TB in HIV patients. Thus MDR-TB in otherwise healthy persons has a mortality nearly equivalent to that in the preantibiotic era and in immunocompromised patients is actually significantly greater! Other infectious diseases are likewise becoming more resistant to chemotherapy so that a number of infectious disease experts fear a return to the perilous conditions of the preantibiotic era. Should anything like this occur, it will be recognized that we collectively have squandered a wonderful opportunity. In poorer nations, the picture has been different. Here the story of this century has been less salubrious. Despite some spotty decrease in TB incidence, the disease has exacted a continuously terrible toll. Statistics demonstrate that despite a century of effort, today TB is the most lethal infection world wide due to a single agent, even surpassing malaria. There can be no doubt that a reinstitution of preventive measures and the discovery of effective new agents are urgently needed in order to deal with this situation.

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