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.
Keywords: Artemisinin; Combination therapy; Membrane damage; Peroxides; Rifampicin; Synergy.
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