Center for Tuberculosis Research, Department of Medicine, Johns Hopkins Universitygrid.21107.35grid.471401.7 School of Medicine, Baltimore, Maryland, USA.
Global Alliance for TB Drug Development, New York, New York, USA.
Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0141221. doi: 10.1128/AAC.01412-21. Epub 2021 Sep 27.
Bedaquiline (BDQ, B) is the first-in-class diarylquinoline to be approved for treatment of tuberculosis (TB). Recent guidelines recommend its use in treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). The newly approved regimen combining BDQ with pretomanid and linezolid is the first 6-month oral regimen proven to be effective against MDR/XDR-TB. However, the emergence of BDQ resistance, primarily due to inactivating mutations in the gene encoding a repressor of the MmpS5-MmpL5 transporter, threatens to undermine the efficacy of new BDQ-containing regimens. Since the shift in MIC due to these mutations is relatively small (2-8×), safer, and more potent, diarylquinoline analogues may be more effective than BDQ. TBAJ-876, which is in phase 1 trials, has more potent activity and a superior pre-clinical safety profile than BDQ. Using a murine model of TB, we evaluated the dose-dependent activity of TBAJ-876 compared to BDQ against the wild-type H37Rv strain and an isogenic loss-of-function mutant. Although the mutation affected the MIC of both drugs, the MIC of TBAJ-876 against the mutant was 10-fold lower than that of BDQ. TBAJ-876 at doses ≥6.25 mg/kg had greater efficacy against both strains compared to BDQ at 25 mg/kg, when administered alone or in combination with pretomanid and linezolid. Likewise, no selective amplification of BDQ-resistant bacteria was observed at TBAJ-876 doses ≥6.25 mg/kg. These results indicate that replacing BDQ with TBAJ-876 may shorten the duration of TB treatment and be more effective in treating and preventing infections caused by mutants.
贝达喹啉（BDQ，B）是首个被批准用于治疗结核病（TB）的一类新型二芳基喹啉类药物。最近的指南建议将其用于治疗耐多药和广泛耐药结核病（MDR/XDR-TB）。新批准的联合贝达喹啉、普托马尼和利奈唑胺的方案是首个被证明对 MDR/XDR-TB 有效的 6 个月口服方案。然而，BDQ 耐药的出现，主要是由于编码 MmpS5-MmpL5 转运蛋白抑制剂的基因发生失活突变，威胁到新的含 BDQ 方案的疗效。由于这些突变导致 MIC 的变化相对较小（2-8×），因此更安全、更有效，二芳基喹啉类似物可能比 BDQ 更有效。目前正在进行 1 期临床试验的 TBAJ-876 具有更强的活性和优越的临床前安全性。我们使用结核分枝杆菌小鼠模型，评估了 TBAJ-876 与 BDQ 对野生型 H37Rv 株和同源失活突变株的剂量依赖性活性。虽然突变影响了两种药物的 MIC，但 TBAJ-876 对突变株的 MIC 比 BDQ 低 10 倍。与 BDQ（25mg/kg）相比，TBAJ-876 在 6.25mg/kg 及以上剂量时，对两种菌株的疗效均优于 BDQ，无论是单独使用还是与普托马尼和利奈唑胺联合使用。同样，在 TBAJ-876 剂量≥6.25mg/kg 时，未观察到 BDQ 耐药菌的选择性扩增。这些结果表明，用 TBAJ-876 替代 BDQ 可能会缩短结核病治疗的持续时间，并在治疗和预防由突变引起的感染方面更有效。
