Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India.
Biochem Pharmacol. 2023 Sep;215:115756. doi: 10.1016/j.bcp.2023.115756. Epub 2023 Aug 19.
Oxidative stress-mediated cell death has remained the prime parasiticidal mechanism of front line antimalarial, artemisinin (ART). The emergence of resistant Plasmodium parasites characterized by oxidative stress management due to impaired activation of ART and enhanced reactive oxygen species (ROS) detoxification has decreased its clinical efficacy. This gap can be filled by development of alternative chemotherapeutic agents to combat resistance defense mechanism. Interestingly, repositioning of clinically approved drugs presents an emerging approach for expediting antimalarial drug development and circumventing resistance. Herein, we evaluated the antimalarial potential of nitrofurantoin (NTF), a clinically used antibacterial drug, against intra-erythrocytic stages of ART-sensitive (Pf3D7) and resistant (PfKelch13) strains of P. falciparum, alone and in combination with ART. NTF exhibited growth inhibitory effect at submicro-molar concentration by arresting parasite growth at trophozoite stage. It also inhibited the survival of resistant parasites as revealed by ring survival assay. Concomitantly, in vitro combination assay revealed synergistic association of NTF with ART. NTF was found to enhance the reactive oxygen and nitrogen species, and induced mitochondrial membrane depolarization in parasite. Furthermore, we found that exposure of parasites to NTF disrupted redox balance by impeding Glutathione Reductase activity, which manifests in enhanced oxidative stress, inducing parasite death. In vivo administration of NTF, alone and in combination with ART, in P. berghei ANKA-infected mice blocked parasite multiplication and enhanced mean survival time. Overall, our results indicate NTF as a promising repurposable drug with therapeutic potential against ART-sensitive as well as resistant parasites.
氧化应激介导的细胞死亡一直是一线抗疟药物青蒿素（ART）的主要寄生虫杀伤机制。由于 ART 激活受损和活性氧（ROS）解毒增强而具有氧化应激管理能力的耐药疟原虫寄生虫的出现，降低了其临床疗效。这一差距可以通过开发替代化学治疗剂来对抗耐药防御机制来填补。有趣的是，重新定位临床批准的药物为加速抗疟药物开发和规避耐药提供了一种新兴方法。在此，我们评估了硝基呋喃妥因（NTF）作为一种临床使用的抗菌药物对青蒿素敏感（Pf3D7）和耐药（PfKelch13）疟原虫株的红内期的抗疟潜力，单独使用和与 ART 联合使用。NTF 在亚微摩尔浓度下通过在滋养体阶段阻止寄生虫生长表现出生长抑制作用。它还通过环存活测定抑制了耐药寄生虫的存活。同时，体外联合测定显示 NTF 与 ART 具有协同作用。发现 NTF 能够增强活性氧和氮物种，并诱导寄生虫中的线粒体膜去极化。此外，我们发现寄生虫暴露于 NTF 会通过阻碍谷胱甘肽还原酶活性来破坏氧化还原平衡，这表现为增强的氧化应激，诱导寄生虫死亡。在 P. berghei ANKA 感染小鼠中单独和联合使用 NTF 进行体内给药可阻断寄生虫繁殖并延长平均存活时间。总体而言，我们的结果表明 NTF 是一种有前途的可重新利用药物，具有针对 ART 敏感和耐药寄生虫的治疗潜力。
