Chemical Class:
Name of Target:
DNA gyrase
Poster presented at ASM Microbe 2017: Session 035, Friday Poster 038. Title: Comparative Evaluation of New Respiratory Quinolone DC-159a or Moxifloxacin Containing Regimens in a Murine TB Model. H. Nakamura, Y. Horita, N. Doi; Japan Anti-Tuberculosis Association, Res. Inst. of Tuberculosis, Tokyo, Japan Abstract: Background: For the assessment of the potential in vivo efficacy of new generation respiratory quinolone DC-159a (D, Daiichi Sankyo Co., Ltd) to shorten the total treatment duration for TB, we conducted a comparative study of Pretomanid (PA-824: P) containing combination regimen PDZ (P: PA-824, D: DC-159a, Z: Pyrazinamide) with Moxifloxacin (M) containing combination regimen PMZ, and current standard regimen RHZ (R: rifampicin, H: isoniazid) using murine TB model. Relapse ratio of each treatment group was also investigated. Methods: Female BALB/c mice (Japan Charles River) were infected with Mycobacterium tuberculosis H37Rv (logCFU=6.04/mouse) via intratracheal route, and treatment was started from Week Four post infection. Treatment groups were: 2PDZ/2PD, 2PMZ/2PM, and 2RHZ/4RH. Dose sizes were: D 50 or 100, M 50, 100 or 200, P 20, R 10, H 10, Z 150 (mg/kg-mouse). Drug cocktail was administered 200 µl/mouse/day, 5 days/week, for 4- or 6-months. Relapse ratio in lung and spleen of the each treatment group (n=10~12/group) was investigated four months after completion of chemotherapy. Results: (1) Lung: PD100Z>PD50Z=RHZ=PM200Z>>PM100Z >PM50Z. PD100Z, PD50Z, RHZ and PM200Z groups negative converted number of CFU after 14-, 16-week treatment, respectively. (2) Spleen: PD100Z>RHZ=PD50Z>PM200Z>PM100Z>>PM50Z. PD100Z, RHZ, PD50Z, PM200Z and PM100Z groups negative converted number of CFU after 8-, 10-, 12- or 16-week treatment, respectively. However, PM50Z group could not negative convert number of CFU in Spleen; recorded final logCFU 1.1. (3) Relapse rate (%): Lung: RHZ: 7.1, PD100Z: 60, PM200Z: 90, PD50Z: 100, PM100Z: 100 and PM50Z: 100% (n=10~14/each group). Spleen: RHZ: 0, PD100Z: 30, PM200Z: 90, PD50Z: 100, PM100Z: 100 and PM50Z: 100% (n=10~14/each group). Conclusions: (1) DC-159a (100mg/kg) combination regimen showed the best efficacy than any other combination groups. (2) DC-159a containing regimens were superior to those of Moxifloxacin containing regimens. (3) DC-159a would shorten the total treatment duration for TB. 2016: DC-159a showed the highest activity against drug-susceptible (DS) TB, quinolone-resistant (QR) MDR-TB and NTM isolates than those of MFLX, GFLX, LVFX and RFP. Activity of DC-159a against QR MDR-TB (MIC90: 0.50 µg/ml) was comparable to that of LVFX against DS-TB isolates. The highest anti-TB activity including MDR strains due to potent inhibitory activity against wild-type and altered DNA gyrase of M. tuberculosis. In the QR MDR-M. tuberculosis infection model, DC-159a treatment groups recorded notable “mean survival days” more than 2~3 times superior to MFLX, LVFX, INH and RFP. In the Drug-Susceptible-M. tuberculosis infection model, DC-159a treatment groups exhibited the best “EBA” and the highest “Log Reduction of CFU in Lungs”, which was superior to those of MFLX, LVFX, INH and RFP. Favorable PK ADME profile, high AUC, Cmax, and target distribution. Superior in vivo efficacy of DC-159a in murine TB models might be attributed to its rapid uptake and high concentrations in lungs.