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FASgen has designed and synthesized a series of novel compounds that not only inhibit the biosynthesis of the tubercle bacillus' waxy outer coating but also interfere with a vital step in the organism's energy-generating metabolic pathways. This mechanism of action differs from all drugs currently used to treat tuberculosis. Thus, it is not surprising that our compounds are very active against even the most drug-resistant strains of TB.
Our lead compound, FAS 20013, is more potent against M.tb. (MIC 0.78 mcg/ml) than several of the currently used drugs. Serum does not attenuate this activity. Further, the compound retains its chemical stability and bactericidal potency in M.tb-infected macrophages in culture over a 72-hour period. Additional studies revealed that FAS 20013 kills Mycobacteria more rapidly than currently used drugs; >99% within 24 hours. This killing is correlated with time of exposure to the compound, not peak concentration. Further, FAS 20013 is equally effective in killing micro-organisms adapted to anoxia, as in latent infections. Resistance to FAS 20013 has not been encountered in clinical isolates nor induced by the usual laboratory techniques. FAS 20013 and back-up compounds are non-toxic to Vero, MCF7 and HepG2 cells in culture in concentrations up to 80 mcg/ml; >60 times their MIC against M.tb. FAS 20013 is >90% orally bioavailable; peak serum concentration is attained within 30 minutes. Serum half-life is ~1.5 hours. Metabolic breakdown in liver microsomes is limited; principal elimination is of unchanged compound via the kidney. To expedite approval, initial clinical trials are planned in patients with acute infections caused by drug resistant organisms because their therapeutic alternatives are very limited or non-existent. These patients are generally isolated to facilitate their overall care and to prevent the spread of their tuberculosis to others. Relatively short treatment trials of three months or less should permit an early evaluation of efficacy and safety of FAS 20013. FASgen has also synthesized compounds that are active against the organism that causes paratuberculosis, a common bowel disease in cattle responsible for losses to the industry of $2 billion annually. Drug development will be undertaken in association with federal and state agricultural departments. Yet another therapeutic opportunity is beginning to emerge as there is mounting evidence that this same organism causes Crohn's disease, a treatment-refractory bowel disorder in humans.
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Tubercle bacilli are shown in cross section and longitudinally by electron microscopy. The arrows point to the normally thick wall of a virulent organism (right) and the wall of a treated organism (left). The treated organism's cell wall has been eroded as one of the FASgen compounds has interfered with its effective biosynthesis. |