Article Figures & Data
Figures
- FIG 1
Structures of clofazimine and TBI-166.
- FIG 2
Activity of TBI-166 against intracellular M. tuberculosis H37Rv.
- FIG 3
Efficacy of TBI-166 in the acute mouse infection model. Dosages are in milligrams per kilogram of body weight. At the beginning of treatment at day 10 postinfection, there were 2.97 ± 0.17 log10 CFU in the lungs of untreated mice. Values were determined after 20 days of treatment in BALB/c mice infected with M. tuberculosis H37Rv.
- FIG 4
Dose-response and kill kinetics of TBI-166 in the chronic mouse infection model. Eight weeks of treatment with vehicle (CMC), 10 mg/kg RIF, 20 mg/kg CFZ, or 10 to 80 mg/kg TBI-166; treatment was initiated on day 28 postinfection. Dosages are in milligrams per kilogram of body weight. All mice were sacrificed prior to treatment or after 2, 4, and 8 weeks of treatment.
- FIG 5
Riminophenazine-induced discoloration of ears in the chronic mouse infection model after 4 weeks of treatment. Ear discoloration of mice after 2 and 8 weeks of administration are presented in Fig. S2 in the supplemental material.
- FIG 6
Riminophenazine-induced discoloration of subcutaneous adipose tissue in the chronic infection model after 4 weeks of treatment. Fat discoloration of the mice after 2 and 8 weeks of administration is presented in Fig. S1.
- FIG 7
Plasma concentrations before dose and 3 h postdose after repeated dosing.
Tables
- TABLE 1
MICs of TBI-166 against different mycobacterial species
Mycobacterial species and/or straina No. of strains MIC data (μg/ml) by drugb TBI-166 CFZ Range Median Range Median M. tuberculosis H37Rv 1 NA 0.063 NA 0.25 M. tuberculosis fully susceptible clinical isolates 16 <0.005–0.15 0.038 0.026–0.633 0.227 M. tuberculosis resistant to RIF 1 NA 0.099 NA 0.224 M. tuberculosis resistant to INH and RIF 2 0.017–0.025 0.021 0.15–0.264 0.207 M. tuberculosis resistant to INH and STR 1 0.018 0.018 0.386 0.386 M. tuberculosis resistant to RIF and EMB 1 NA 0.2 NA 0.3 M. tuberculosis resistant to INH, RIF, and LVX 1 NA 0.026 NA 0.064 M. tuberculosis resistant to INH, RIF, and STR 1 NA 0.1 NA 0.3 M. tuberculosis resistant to RIF, STR, and EMB 1 NA 0.1 NA 0.3 M. tuberculosis resistant to INH, RIF, and EMB 3 0.013–0.098 0.025 0.075–0.3 0.143 M. tuberculosis resistant to RIF, STR, LVX, and EMB 2 0.1–0.164 0.132 0.15–0.544 0.347 M. tuberculosis resistant to INH, RIF, LVX, and EMB 4 0.019–0.05 0.0385 0.095–0.486 0.2425 M. tuberculosis resistant to INH, RIF, STR, and EMB 5 0.01–0.2 0.1 0.15–0.3 0.219 M. tuberculosis resistant to INH, RIF, STR, LVX, and EMB 6 0.039–0.2 0.1125 0.118–0.844 0.4095 M. kansasii 1 NA 0.183 NA 1.776 M. scrofulaceum 1 NA 1.49 NA 0.292 M. fortuitum 1 NA 0.688 NA 0.276 - TABLE 2
MICs for CFZ and TBI-166 against rv0678 mutant and wild-type M. tuberculosis strains
Strain Sequence or mutation by gene MIC (μg/ml) by drug rv0678 pepQ atpE Bedaquiline CFZ TBI-166 BDQ-1 C305T WT WT 0.49 1.34 0.18 BDQ-2 292–316 nt deletion WT WT 0.47 1.29 0.19 BDQ-3 C403T WT WT 0.47 1.62 0.19 H37Rv WT WT WT 0.06 0.14 0.060 - TABLE 3
Distribution and accumulation of 20 mg/kg TBI-166 and CFZ in uninfected mice after 2, 4, and 8 weeks of exposure
Drug Infection site Concn (μg/g) by exposure time 2 wk 4 wk 8 wk TBI-166 Lung 27.12 ± 6.15 28.91 ± 12.33 44.28 ± 12.62 CFZ 7.92 ± 7.10 31.87 ± 2.82 32.88 ± 10.28 TBI-166 Liver 32.29 ± 9.68 53.60 ± 42.66 108.17 ± 46.93 CFZ 2.01 ± 0.92 4.94 ± 2.02 12.75 ± 0.87 TBI-166 Spleen 27.98 ± 11.17 16.83 ± 15.39 36.54 ± 19.52 CFZ 13.18 ± 3.35 33.30 ± 0.97 36.47 ± 4.71 TBI-166 Fat 576.45 ± 307.52 1,336.34 ± 503.18 CFZ 180.07 ± 88.66 253.27 ± 28.50 TBI-166 Skin 103.51 ± 71.50 169.23 ± 15.91 CFZ 47.78 ± 19.67 41.57 ± 13.88
Supplemental material
- Supplemental file 1 -
Fig. S1 and S2 and Tables S1 and S2
PDF, 457K
- Supplemental file 1 -
