Liu H T, Fu L, Wang B, Wang N, Li D S, Ding Y M, Yao R, Qi X T, Lu Y
Beijing Chest Hospital, Capital Medical University, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.
Zhonghua Jie He He Hu Xi Za Zhi. 2022 Jun 12;45(6):560-566. doi: 10.3760/cma.j.cn112147-20211008-00697.
To evaluate two-drug combination interaction between pyrifazimine(TBI-166) and anti-drug-resistant tuberculosis group A drugs Bedaquiline (BDQ), Moxifloxacin (MFX) and the new anti-tuberculosis drug Delamanid (DLM), SQ109, Q203, and PBTZ169 and in mouse, so as to provide basis for TBI-166 combination therapy. This study was performed from September 2020 to July 2021. The chessboard method was used to evaluate the interaction between TBI-166 and BDQ, MFX, DLM, SQ109, and PBTZ169. The time-killing kinetics method was used to evaluate the anti-tuberculosis activity of the two-drug combination with partial synergy. The BALB/c mouse acute infection model was used to evaluate the anti-tuberculosis activity at 4 and 8 weeks in the two-drug combination group (TBI-166+BDQ, TBI-166+SQ109, TBI-166+PBTZ169, TBI-166+Q203) and monotherapy groups (TBI-166, BDQ, SQ109, PBTZ169, Q203). Data analysis was performed using an independent sample test. After TBI-166 combined with anti-tuberculosis drugs, MIC was reduced to 6.25% to 25.00% of TBI-166 monotherapy. After TBI-166 combined with BDQ, SQ109 and PBTZ169, the partial inhibitory concentration index (FICI) values were 0.53, 0.75 and 0.75, respectively; the time sterilization experiment showed that the viable population of treated with two-drug combination of TBI-166 and BDQ, SQ109, PBTZ169 for 14 days decreased at least 3 log CFU/ml. In the mouse experiments, it was found that, the amount of viable bacteria in lung tissue of BDQ, SQ109 and PBTZ169 combined with TBI-166 groups was lower than that of the monotherapy group,respectively. The lung tissue culture of mice in the TBI-166+BDQ group was negative after 4 weeks of treatment, and the number of live bacteria in the lungs of the TBI-166+BDQ group was 1.49 logCFU lower than that of the BDQ monotherapy group(<0.01). and experiments in mice revealed that TBI-166 had synergistic anti-tuberculosis activity after being combined with BDQ, SQ109 and PBTZ169, respectively.
为评估吡嗪胺（TBI-166）与抗耐药结核病A组药物贝达喹啉（BDQ）、莫西沙星（MFX）、新型抗结核药物德拉马尼（DLM）、SQ109、Q203和PBTZ169的两药联合相互作用，在小鼠体内进行研究，为TBI-166联合治疗提供依据。本研究于2020年9月至2021年7月进行。采用棋盘法评估TBI-166与BDQ、MFX、DLM、SQ109和PBTZ169之间的相互作用。采用时间杀菌动力学方法评估具有部分协同作用的两药联合的抗结核活性。使用BALB/c小鼠急性感染模型评估两药联合组（TBI-166+BDQ组、TBI-166+SQ109组、TBI-166+PBTZ169组、TBI-166+Q203组）和单药治疗组（TBI-166组、BDQ组、SQ109组、PBTZ169组、Q203组）在4周和8周时的抗结核活性。采用独立样本检验进行数据分析。TBI-166与抗结核药物联合后，MIC降至TBI-166单药治疗的6.25%至25.00%。TBI-166与BDQ组、SQ109组和PBTZ169组联合后的部分抑菌浓度指数（FICI）值分别为0.53、0.75和0.75；时间杀菌实验表明，TBI-166与BDQ组、SQ109组、PBTZ169组两药联合处理14天后的活菌数至少减少3 log CFU/ml。在小鼠实验中发现，BDQ组、SQ109组和PBTZ169组与TBI-166联合组肺组织中的活菌量分别低于单药治疗组。TBI-166+BDQ组小鼠治疗4周后肺组织培养为阴性，TBI-166+BDQ组肺内活菌数比BDQ单药治疗组低1.49 logCFU（<0.01）。小鼠实验表明，TBI-166分别与BDQ、SQ109和PBTZ169联合后具有协同抗结核活性。
