In Vivo Efficacy of DC-159a, a New Generation of Respiratory Quinolone, against Experimental Murine Tuberculosis due to Multi-Drug-Resistant Mycobacterium tuberculosis

N H2 OMe Me 1/2 H2O The concentration and lung/serum ratio of DC-159a in CBA/JNCrlj mice were higher than those of MFLX, LVFX and gemifloxacin, described in Kurosaka et al. (the 46th ICAAC, poster No. F1-0489). As in the case of CBA/JNCrlj mice, DC-159a showed high concentrations in BALB/c mice after oral dosing. Accorded with the promising in vitro activity against M. tuberculosis isolates shown in poster No. F1-0491, DC-159a proved its potent anti-M. tuberculosis activity in murine tuberculosis models. In a series of in vivo studies, dose sizes of DC-159a, from 25 to 100mg/kg-mouse/day were settled on the basis of the pharmacokinetic (PK) studies. In the Quinolone-Resistant-MDR-M. tuberculosis infection model, DC-159a exhibited bacteriostatic activity in lungs, and was specifically better in lungs than those of liver and spleen (data not shown). In comparative study of the mean survival days by QR-MDR-TB infection model, DC-159a treatment groups recorded notable superior results in contrast to those of the existing drugs: MFLX, LVFX, INH and RFP. In the EBA (Early-Bactericidal-Activity) study by Drug-Susceptible M. tuberculosis infection model, DC159a 50mg/kg treatment demonstrated an equivalent efficacy to that of MFLX 100mg/kg treatment. In addition, all the DC-159a treatment groups, at 25, 50 and 100mg/kg, enhanced their bactericidal activity continuously from 3to 9days. On the contrary, MFLX could not promote “Log Reduction of CFU in lungs” from 3to 9-days. Considering the characteristic PK profiles of DC-159a, superior in vivo efficacy of DC-159a in murine TB models might be attributed to its rapid uptake and high concentration in lung tissue. The experimental results reported above bring us an encouraging scope for the future direction of “the new standard chemotherapy regimen for TB” as well as treatment of MDR-TB and QR-MDR-TB cases. To shorten the total treatment duration as possible, in combination with the existing first-line drugs and/or another novel candidate, further preclinical study of DC-159a is in progress. ABSTRACT