Therapeutic efficacy of benzoxazinorifamycin, KRM-1648, in combination with other antimicrobials against Mycobacterium leprae infection induced in nude mice.

In this study, the in vitro and in vivo anti-Mycobacterium leprae activity of the newly developed benzoxazinorifamycin, KRM-1648, in combination with clofazimine (CFZ) or dapsone (DDS) was evaluated. In vitro anti-M. leprae activities of KRM-1648, CFZ, and DDS along with their combinations were measured by the BACTEC 460 TB System. KRM-1648 (0.01 microgram/ml), CFZ (0.5 microgram/ml), and DDS (2.0 micrograms/ml exhibited a significant anti-M. leprae activity, reducing growth index (GI) values by 78%, 30%, and 35% by day 18, respectively. Combinations of KRM-1648 with either CFZ or DDS, or both caused only a slight increase in the efficacy. BALB/c nude mice infected subcutaneously with 1 x 10(6) of M. leprae Thai-53 strain and test drugs were given to mice by gavage once daily six times per week for up to 50 days, from day 31 to day 80. Animals were observed for the growth of organisms in the hindfoot pad during the 12 months following infection. KRM-1648 given at the dose of 0.001 mg/mouse exhibited potent antileprosy activity. KRM-1648 exhibited a significant combined effect with either CFZ or DDS, or both against M. leprae infection, except that there was no significant difference in efficacy between KRM-1648 + CFZ and CFZ alone. Furthermore, the efficacy was most increased in the three-drug regimen KRM-1648 + CFZ + DDS.