Bedaquiline

Bedaquiline is a diarylquinoline-class anti-tuberculosis drug. Bedaquiline works by inhibiting the ATP synthase of Mycobacterium tuberculosis, thereby blocking the bacterium's energy supply^[1-2]. Bedaquiline is applicable for research related to multidrug-resistant tuberculosis (MDR-TB) and cancer^[3-4].

In vitro, treatment of MCF7 breast cancer cells with Bedaquiline (1–10µM) for 48 hours inhibited mitochondrial oxygen consumption and glycolysis, induced oxidative stress, and significantly suppressed the proliferation and expansion of MCF7-derived cancer stem-like cells (CSCs). Treatment of normal human fibroblasts (hTERT-BJ1) with Bedaquiline (10µM) for 48 hours increased oxygen consumption, ATP levels, and glycolysis in hTERT-BJ1 cells without inducing significant stress responses^[5]. Treatment of non-small cell lung cancer cell lines H1299 and A549 with Bedaquiline (2.5–50µM) for 72 hours inhibited cell viability and caused cell death in H1299 cells, while also suppressing mitochondrial respiration and glycolysis; in A549 cells, no cytotoxicity was observed at the tested concentrations^[6].

In vivo, Bedaquiline (10mg/kg or 25mg/kg) was administered orally five times per week for 4 weeks to BALB/c mice that had been infected via low-dose aerosol with the Mycobacterium tuberculosis Erdman strain. In BALB/c mice, Bedaquiline treatment significantly and uniformly reduced the bacterial load in the lungs^[7]. Bedaquiline (30mg/kg) was administered orally for 12-25 days to C3HeB/FeJ mice that had been intravenously infected with Mycobacterium abscessus. Bedaquiline reduced the bacterial burden in the lungs and spleen more significantly than amikacin (150mg/kg; subcutaneous injection)^[8].

References:
[1] Conradie F, Bagdasaryan TR, Borisov S, et al. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1;387(9):810-823.
[2] Khoshnood S, Goudarzi M, Taki E, et al. Bedaquiline: Current status and future perspectives. J Glob Antimicrob Resist. 2021 Jun;25:48-59.
[3] Zhu H, Chen Q, Zhao L, et al. Targeting ATP Synthase by Bedaquiline as a Therapeutic Strategy to Sensitize Ovarian Cancer to Cisplatin. Nutr Cancer. 2023;75(4):1271-1280.
[4] Lange C, Vasiliu A, Mandalakas AM. Emerging bedaquiline-resistant tuberculosis. Lancet Microbe. 2023 Dec;4(12):e964-e965.
[5] Fiorillo M, Lamb R, Tanowitz HB, et al. Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). Aging (Albany NY). 2016 Aug;8(8):1593-607.
[6] Parvathaneni V, Elbatanony RS, Goyal M, et al. Repurposing Bedaquiline for Effective Non-Small Cell Lung Cancer (NSCLC) Therapy as Inhalable Cyclodextrin-Based Molecular Inclusion Complexes. Int J Mol Sci. 2021 Apr 30;22(9):4783.
[7] Irwin SM, Prideaux B, Lyon ER, et al. Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice. ACS Infect Dis. 2016 Apr 8;2(4):251-267.
[8] Le Moigne V, Raynaud C, Moreau F, et al. Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice. Antimicrob Agents Chemother. 2020 May 21;64(6):e00114-20.

Bedaquiline是一种二芳基喹啉类抗结核药物。Bedaquiline可通过抑制结核分枝杆菌ATP合成酶来阻断细菌能量供应^[1-2]。Bedaquiline可用于耐多药结核病和癌症的相关研究^[3-4]。

在体外，Bedaquiline（1–10µM）处理MCF7乳腺癌细胞48小时，可抑制细胞线粒体氧消耗和糖酵解，同时诱导氧化应激，并显著抑制MCF7来源的癌症干细胞样细胞的增殖。Bedaquiline（10µM）处理正常人类成纤维细胞（hTERT-BJ1）48小时，可增强hTERT-BJ1细胞的氧消耗、ATP水平和糖酵解，且不诱导明显的应激反应^[5]。Bedaquiline（2.5–50µM）处理非小细胞肺癌细胞系H1299和A549 72小时。在H1299细胞中，Bedaquiline可抑制细胞活力并导致细胞死亡，同时能够抑制线粒体呼吸和糖酵解；在A549细胞中，Bedaquiline于测试浓度下未观察到细胞毒性^[6]。

在体内，Bedaquiline（10mg/kg或25mg/kg）以口服方式每周给药五次，用于处理经低剂量气溶胶感染结核分枝杆菌Erdman菌株的BALB/c小鼠4周。在BALB/c小鼠中，Bedaquiline治疗能显著且均匀地减少肺部细菌载量^[7]。Bedaquiline（30mg/kg）以口服方式给药于经静脉感染Mycobacterium abscessus的C3HeB/FeJ小鼠12-25天。Bedaquiline能比阿米卡星（150mg/kg；皮下注射）更显著地减少肺和脾中的细菌负荷^[8]。