Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0065822. doi: 10.1128/aac.00658-22. Epub 2022 Aug 4.
TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.
TBI-166 是一种源自利米吩嗪类似物的化合物，其抗结核活性比氯法齐明更强，目前正在中国进行 IIa 期临床试验评估。含有 TBI-166 的临床前方案研究将支持 TBI-166 的 IIb 期临床试验。在本研究中，我们比较了三种小鼠结核病模型中，TBI-166 联合贝达喹啉（BDQ）和吡嗪酰胺（PZA）的全口服耐药结核病药物方案与异烟肼（INH）联合利福平（RFP）和 PZA（HRZ 方案）一线方案、最有效的 TBI-166 联合 BDQ 和利奈唑胺（LZD）方案、BDQ 联合丙硫异烟胺和 LZD 的 Nix-TB 临床试验方案（BPaL 方案）的疗效。在 C3HeB/FeJ 小鼠结核病模型中，TBI-166+BDQ+PZA 方案治疗 4 周时肺部培养阴性，8 周时无复发。细菌负荷减少率和复发率均大于 HRZ 方案和 TBI-166+BDQ+LZD 方案。与 BPaL 方案相比，TBI-166+BDQ+PZA 方案在 BALB/c 小鼠结核病模型中具有相似或更强的早期杀菌活性、杀菌活性和灭菌活性。TBI-166+BDQ+PZA 方案组细菌负荷下降明显多于 BPaL 方案组，几乎或完全无复发（8 周后<13.33%）。总之，确定了包括具有高效性的 TBI-166 在内的口服短程三药方案。建议进一步在 TBI-166 的 IIb 期临床试验中研究 TBI-166+BDQ+PZA 方案。
