TB47 and clofazimine form a highly synergistic sterilizing block in a second-line regimen for tuberculosis in mice
| Autor: | Wei Yu, Lingmin Guo, Zhili Lu, Shahzad Akbar Khan, Nanshan Zhong, Gift Chiwala, Sanjeep Sapkota, Zhiyong Liu, Tianyu Zhang, Gao Yamin |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
TB47 Pyridines medicine.drug_class Antibiotics Antitubercular Agents Respiratory chain Microbial Sensitivity Tests RM1-950 Drug resistance Pharmacology Clofazimine Mice 03 medical and health sciences 0302 clinical medicine Recurrence Levofloxacin Tuberculosis Multidrug-Resistant medicine Animals Ethambutol Regimen Mice Inbred BALB C business.industry Imidazoles Drug Synergism Mycobacterium tuberculosis General Medicine Pyrazinamide Disease Models Animal Synergy 030104 developmental biology 030220 oncology & carcinogenesis Female Therapeutics. Pharmacology business medicine.drug |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 131, Iss, Pp 110782-(2020) |
| ISSN: | 0753-3322 |
| DOI: | 10.1016/j.biopha.2020.110782 |
| Popis: | Multidrug-resistant tuberculosis (MDR-TB) remains a serious public health threat worldwide. To date, the anti-TB activity of TB47 (T), an imidazopyridine amide class of antibiotics targeting QcrB in the electron transport chain, has not been systematically evaluated, especially in a new regimen against MDR-TB. This study employed both macrophage infection and a mouse model to test the activity of T alone or in combination with other antimicrobial agents. Different regimens containing amikacin (A), levofloxacin (L), ethambutol (E), and pyrazinamide (Z) + clofazimine (C)/T were evaluated in the mouse model. The bacterial burdens of mice from different groups were monitored at different time points while relapse was assessed 6 months after treatment cessation. Colonies obtained at relapse underwent drug susceptibility testing. We found that T exhibited highly synergistic bactericidal activity with C in all models. Adding T to ALEZC might shorten the MDR-TB treatment duration from ≥ 9 months to ≤ 5months, as five months of treatment with ALEZCT achieved zero relapse rates in 2 animal experiments. These findings indicate that T exhibits a highly synergistic sterilizing activity when combined with C. All isolates from relapsing mice remained sensitive to each drug, suggesting that the relapse was not due to drug resistance but rather associated with the type of regimen. |
| Databáze: | OpenAIRE |
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