Activities Of KRM-1648 Research Articles

Effects of half-sized secretory leukocyte protease inhibitor and Chinese traditional medicines, yokuinin and mao-bushi-saishin-to, on therapeutic efficacies of benzoxazinorifamycin KRM-1648 against Mycobacterium avium complex infection induced in mice

We examined the effects of such drugs having anti-inflammatory activity as half-sized secretory leukocyte protease inhibitor (1/2 SLPI) and Chinese traditional medicines, Yokuinin (YOK) and Mao-Bushi-Saishin-To (MBST), on therapeutic efficacies of benzoxazinorifamycin KRM-1648 against Mycobacterium avium complex (MAC) infection induced in mice, since it is possible that these agents inhibit the increase in tissue levels of immunosuppressive cytokines due to MAC infection. First, Zymosan A-induced murine peritoneal macrophages treated with either 1/2 SLPI, YOK or MBST at 37 degrees C for 2 days were infected with M. avium N-444 and further cultivated in the medium with or without addition of 1/2 SLPI, YOK or MBST at 37 degrees C for up to 7 days. Treatment of macrophages with these drugs caused some decrease in the intracellular growth of the organisms. Secondly, we evaluated effects of 1/2 SLPI, YOK and MBST on the therapeutic efficacy of benzoxazinorifamycin KRM-1648 against M. avium infection induced in mice. When MAC-infected mice were given KRM-1648 (20 mg/kg) alone, or in combination with 1/2 SLPI (100 mg/kg), YOK (50 mg/kg), or MBST (50 mg/kg), by gavage, except for 1/2 SLPI which was given via i.p. route, once a week, from day 1 for up to 8 weeks after infection, these drugs did not affect the expression of therapeutic activity of KRM-1648. When MAC-infected mice were given KRM-1648 alone (once a week), or in combination with YOK (five times per week) or MBST (five times per week), MBST increased the expression of therapeutic activity of KRM-1648. These findings indicate that suppression of inflammatory reactions using MBST is capable to improve the therapeutic efficacy of KRM-1648 in MAC infection. Moreover, these results also mean that combined use of these drugs in MAC patients receiving KRM-1648 therapy may not cause any disadvantages to the therapeutic efficacy of KRM-1648.

Differential effect of rpoB mutations on antibacterial activities of rifampicin and KRM-1648 against Staphylococcus aureus.

The in vitro antibacterial activities of the rifamycin derivatives rifampicin and KRM-1648 against 150 Staphylococcus aureus isolates were determined. The MICs of rifampicin and KRM-1648 for 90% of rifampicin-susceptible S. aureus isolates (n = 100) were 0.016 and 0.001 mg/L, respectively. In rifampicin-resistant S. aureus isolates (n = 50), different levels of resistance to rifamycins were associated with mutations at different sites in rpoB. Mutations at some sites were associated with high-level resistance to both rifamycins, while certain mutations were associated with the activity of KRM-1648 being < or = 100-fold better than that of rifampicin.

Antimicrobial activities of benzoxazinorifamycin KRM-1648, clarithromycin and levofloxacin against intracellular Mycobacterium avium complex phagocytosed by murine peritoneal macrophages.

The in-vitro activities of KRM-1648, a new benzoxazinorifamycin, clarithromycin and levofloxacin against clinical isolates of Mycobacterium avium complex (MAC) were measured using various methods of assay and compared with their in-vivo therapeutic activities against MAC infection in mice. The MICs varied according to drug in the order KRM-1648 << clarithromycin < levofloxacin. However, KRM-1648 and clarithromycin but not levofloxacin had similar therapeutic outcomes in MAC-infected mice. KRM-1648 and clarithromycin given at clinical dosages caused 1 to 2 log unit reductions in bacterial loads in the lungs of host mice. The values of Cmax (lung)/MBC were more closely related to the therapeutic efficacy of these drugs in mice than were MICs and MBCs alone. Potent microbicidal activity was observed with KRM-1648 and clarithromycin but not with levofloxacin against extracellularly growing MAC (EG-MAC) in a liquid medium. These two agents caused more than 3 log unit killing of MAC during a 5 day incubation, when added at concentrations equivalent to Cmax (lung). The anti-EG-MAC bactericidal activity of these drugs was greater than their efficacy in mice in vivo. KRM-1648 and clarithromycin but not levofloxacin caused respectively 2 and 0.5 log unit killing of intracellularly growing MAC (IG-MAC) in murine peritoneal macrophages. The profiles of bacterial killing effects of these agents against IG-MAC accurately reflected their therapeutic effects in mice, although the in-vivo activity of KRM-1648 was still overestimated using even this parameter.

Activity of KRM-1648, a new benzoxazinorifamycin, against Mycobacterium tuberculosis in a murine model

The activity of KRM-1648 was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 week postinfection and given by gavage for 4 weeks. Viable-cell counts were determined from homogenates of spleen and lung tissues. The activity of KRM-1648 was compared with those of rifampin and rifabutin at 20 mg/kg of body weight. KRM-1648 was more active than either rifampin or rifabutin against organisms in spleens and lungs. KRM-1648 alone and in combination with either isoniazid, ethambutol, pyrazinamide, or levofloxacin was evaluated. Other treatment groups received isoniazid, ethambutol, pyrazinamide, or levofloxacin as single agents. KRM-1648 was the most active single agent evaluated. KRM-1648-pyrazinamide and KRM-1648-isoniazid were the most active combinations. These combinations were more active than KRM-1648 alone. The promising activity of KRM-1648 in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent.