Current status in the development of new antituberculosis drugs

Abstract

Tuberculosis (TB) is still the greatest single infectious cause of mortality worldwide. However, powerful new anti-TB drugs with new mechanisms of action have not been developed in the last over thirty years. It is expected that development of new effective anti-TB drugs will bring us various outcomes such as shortening the total treatment duration, improvement of the treatment completion ratio, prevention and treatment of multidrug-resistant tuberculosis (MDR-TB) and reducing overall medical expenditures. A new anti-TB drug needs to show good pharmacokinetic distribution and permeation into lung tissue and cells. Furthermore, it is also desired that novel candidate exhibits the potent bactericidal activity both against exponential and stable phases of Mycobacterium tuberculosis in vivo. In addition, it is ideal thatthe novel agent possesses a narrow antimicrobial spectrum targeting only the Mycobacterial species. Nitroimidazopyran is the center of attention in the world today as a most potent drug candidate for TB. Its leading compound, PA-824, is being developed in clinical trial phase I. PA-824 has two mechanisms; inhibitions of the biosynthesis of protein and cell wall lipid of M. tuberculosis. It exhibits bactericidal activity against both replicating and static M. tuberculosis. It also shows potent bactericidal activity against MDR-M. tuberculosis. Among new rifamycin derivatives, rifalazil (KRM-1648) the most promising drug candidate, is being developed in clinical trial phase II. Rifalazil demonstrates potent long-acting oral activity against M. tuberculosis both in animal models and humans. Gatifloxacin (GFLX) and moxifloxacin (MXFX), 8-methoxy-fluoroquinolone representatives, show bactericidal activity against replicating M. tuberculosis both in vitro and in murine tuberculosis models. ABT-773 and HMR-3647, ketolide compound representatives possess potential bactericidal activity against Mycobacterium avium-intracellulare complex (MAC) in vitro, but these ketolide compounds are ineffective against macrolide-resistant MAC strains. Caprazamycin-B (CPZ-B) is a promising novel antibiotic recently developed in Japan, which was isolated from Streptomyces species. In contrast to current anti-TB drugs, CPZ-B has a novel chemical structure with specific bactericidal activity against Mycobacterial species, especially M. tuberculosis including MDR strains and MAC isolates. CPZ-B inhibits cell wall biosynthesis of Mycobacteria, and exhibits moderate therapeutic efficacy that is dose size dependent in a murine pulmonary tuberculosis model. Any cytotoxicity is not observed in preceding animal experiments. “The Global Alliance for TB Drug Development (GATB)”, formed organization under a WHO initiative, started funding pharmaceutical companies to develop the novel agents for TB. GATB recently set up a new project, “Aerosolized new drug in DDS”. It has a potentially promising scope for developing new anti-TB drugs and managing chemotherapy as well.