New drugs being developed for the treatment of tuberculosis

Abstract

More than one-third of the world is infected with tuberculosis (TB) and 5000 people die of TB everyday. Of the many diarylquinolones shown to be effective at inhibiting the multiple-cycle growth of Mycobacterium tuberculosis, R-207910 was the most active and was chosen as the lead compound. In the non-established infection mouse TB model, a single dose of R-207910 50 mg/kg had a bacteriostatic effect, and a bactericidal effect was observed at 100 mg/kg. In the established infection mouse model, treatment was started 12 – 14 days after infection, and when added to the triple therapy of isoniazid, rifampin and pyrazinamide or substituted for any component of the triple therapy, R-207910 increased the effectiveness. As ethambutol is chemically simple, and only has modest potency in treating TB, it was considered to be amenable to optimisation by combinatorial chemistry, and from the analogues synthesised that inhibited the growth of M. tuberculosis, SQ-109 was eventually selected as the lead compound for further testing. In female mice infected with M. tuberculosis H37Rv by tail-vein injection, treatment with SQ-109 25 mg p.o. initiated 20 days later for 5 days/week for 4 weeks reduced the counts by 1.87 log units, which was slightly more than with ethambutol 100 mg (1.67 log units). These results indicate that exciting new drugs are under development for the treatment of TB.

Keywords::

• mouse TB models
• Mycobacterium tuberculosis
• R-207910
• SQ-109
• tuberculosis