Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility - PubMed (original) (raw)
Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility
Bai-Yu Lee et al. PLoS One. 2018.
Abstract
As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis.
Conflict of interest statement
With respect to patent protection, we note that we have one patent and one patent application as follows: 1) U.S. Patent 10,080,749: Multi-drug therapies for tuberculosis treatment. 2) U.S. Provisional Application Serial No. 62/485,859: Multi-drug combinations for tuberculosis treatment. We confirm: This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Figures
Fig 1. Drug-dose efficacy response surface of PRS Regimen III.
(A) Lung log10 CFU from BALB/c mice (n = 5 per group) that were sham-treated or treated with the Standard Regimen (SR), PRS Regimen II (PRS II) or PRS Regimen III. Each of the twelve groups of mice treated with PRS Regimen III received the same 4-drug combination with CFZ kept constant at 25 mg/kg and the three other drugs, SQ109, BDQ and PZA, administered at high (H), middle (M), high-middle (H-M) or low (L) dose as shown in Table 1. One mouse each in the groups treated with PRS Regimen III at a dose ratio of HHHH, HLHH, and HMHH had zero CFU in the entire lung; for these mice, a lung CFU count of 1 was assigned for calculation of log10 CFU. (B) 3-D surface depicts relationship between doses of two drugs in PRS Regimen III (x and y axes) and projected log10 CFU (z axis). One-way ANOVA with Tukey’s multiple comparison test was used in statistical analyses. **** p < 0.0001.
Fig 2. Long-term efficacy (Time to Lung Sterilization) and relapse (Time to Relapse-free Cure) study in BALB/c mice.
(A) Lung burden of M. tuberculosis after 3, 4, 5, and 6 weeks of sham treatment or treatment with the Standard Regimen (SR), PRS Regimen II (PRS II) or PRS Regimen III (PRS III). For mice that had zero CFU in the lungs, a CFU count of 1 was assigned for graphing purposes. Two-way ANOVA with Tukey’s multiple comparison test was used in statistical analyses. **** p < 0.0001, ns, not significant (B) Lung burden of M. tuberculosis over the course of infection and treatment. (C) Relapse. Total number of M. tuberculosis in the lung of each mouse was determined three months after treatment cessation. Relapse is defined as 1 or more CFU per lung. For all PRS Regimen II groups, PRS Regimen III groups at 5 and 6 weeks, and for the Standard Regimen groups at 8, 12, 16, and 22 weeks, n = 10 mice/group. For the PRS Regimen III group at 3 and 4 weeks, n = 9 and n = 8 mice/group, respectively, and for the Standard Regimen group at 20 weeks, n = 14 mice/group. (p <0.0001, PRS Regimen III or PRS Regimen II versus Standard Regimen, log rank test).
Fig 3. Lung gross pathology in BALB/c mice upon completion of 4 weeks of treatment.
Mice (n = 5 per group) were infected with M. tuberculosis by aerosol and starting two weeks later, they were either sham-treated or treated with the Standard Regimen (INH/RIF/EMB/PZA at 25/10/100/150 mg/kg), PRS Regimen II (CFZ/BDQ/EMB/PZA at 25/30/100/450 mg/kg) or PRS Regimen III (CFZ/BDQ/SQ109/PZA at 25/30/25/450 mg/kg) 5 days per week for 4 weeks. Their lungs and surface granulomas were photographed for inspection. Scale bar (upper left panel), 1 cm.
Fig 4. Treatment efficacy and Time to Relapse-free Cure study in C3HeB/FeJ mice.
(A) Lung burden of M. tuberculosis after treatment daily for 14 days or 5 days per week for 3, 4, 5, 6 and 8 weeks in sham-treated mice or mice treated with the Standard Regimen (SR) or PRS Regimen III (PRS III), d, daily. Two-way ANOVA with Tukey’s multiple comparison test was used in statistical analyses. **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05, ns, not significant (B) Lung burden of M. tuberculosis over the course of infection and treatment. d, daily (C) Total number of M. tuberculosis in the lung of each mouse was determined three months after treatment cessation. Relapse is defined as 1 or more CFU per lung. For the Standard Regimen group at 8 weeks, and PRS Regimen III groups at 4 and 6 weeks, n = 10 mice/group. For Standard Regimen group at 6 week, n = 8 mice/group, and the PRS Regimen III group at 5 weeks, n = 9 mice/group. (p <0.0001, PRS Regimen III versus Standard Regimen, log rank test).
Fig 5. Lung gross pathology in C3HeB/FeJ mice upon completion of 4 weeks of treatment.
Mice (n = 5 per group) were infected with M. tuberculosis by aerosol and starting six weeks later, they were either sham-treated or treated with the Standard Regimen (INH/RIF/EMB/PZA at 25/10/100/150 mg/kg), PRS Regimen II (CFZ/BDQ/EMB/PZA at 25/30/100/450 mg/kg) or PRS Regimen III (CFZ/BDQ/SQ109/PZA at 25/30/25/450 mg/kg) 5 days per week for 4 weeks. Their lungs and surface granulomas were photographed for inspection. Note that granulomas of the sham treated mice are much larger in the C3HeB/FeJ mice than the BALB/c mice in Fig 3. Scale bar (upper left panel), 1 cm.
References
- Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med. 1990;112: 397–406. -PubMed
- World Health Organization. Global Tuberculosis Report 2016. 2016. Available from: http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?...
- World Health Organization. The Shorter MDR-TB Regimen. 2016. Available from: http://www.who.int/tb/Short_MDR_regimen_factsheet.pdf
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