Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, 400076, Maharashtra, India.
Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, 400076, Maharashtra, India; Wadhwani Research Center for Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India.
Tuberculosis (Edinb). 2019 Mar;115:146-153. doi: 10.1016/j.tube.2019.03.004. Epub 2019 Mar 14.
The current anti-TB treatment consists of a prolonged multi-drug therapy. Interventional strategies are required to reduce the chemotherapeutic load. In this regard, we have previously identified a synergistic interaction between hydroperoxides and rifampicin. This strategy has been extended here to repurpose a new drug against TB. A hydrophobic antimalarial drug, artemisinin, with an unstable endoperoxide bridge structure, has been investigated as a potential candidate. In combination with rifampicin, artemisinin was found to be synergistic against M. bovis BCG and M. tuberculosis H37Ra. Furthermore, artemisinin was observed to induce peroxides in a time and concentration dependent manner and the levels of the peroxides were significantly higher in cells treated with the drug pair. Coupled with rapid disintegration of the membrane, this enhanced the clearance of the bacterial culture in vitro. On the other hand, formation of the peroxides was significantly reduced in the presence of ascorbic acid, an antioxidant. This translated to a loss of the synergistic effect of the combination, indicating the importance of peroxide formation in the mode of action of artemisinin. Interestingly, artemisinin also had a synergistic interaction with isoniazid, amikacin and ethambutol and an additive interaction with moxifloxacin, other drugs commonly used against TB.
目前的抗结核治疗包括长期的多药物治疗。需要介入策略来降低化疗负荷。在这方面，我们之前已经确定了过氧化物和利福平之间的协同相互作用。这一策略在这里被扩展到重新利用一种新的抗结核药物。青蒿素是一种具有不稳定的内过氧化物桥结构的疏水抗疟药物，被认为是一种潜在的候选药物。研究发现，青蒿素与利福平联合使用对牛分枝杆菌 BCG 和结核分枝杆菌 H37Ra 具有协同作用。此外，青蒿素被观察到以时间和浓度依赖的方式诱导过氧化物，并且在用药物对处理的细胞中过氧化物的水平明显更高。与膜的快速崩解相结合，这增强了体外细菌培养物的清除。另一方面，在抗氧化剂抗坏血酸存在下，过氧化物的形成显著减少。这导致组合的协同作用丧失，表明过氧化物形成在青蒿素作用模式中的重要性。有趣的是，青蒿素还与异烟肼、阿米卡星和乙胺丁醇具有协同相互作用，与莫西沙星（一种常用于抗结核的药物）具有相加相互作用。
