Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur 844102, India.
Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Agamkuan, Patna, Bihar 800007, India.
Oxid Med Cell Longev. 2018 Feb 25;2018:4074357. doi: 10.1155/2018/4074357. eCollection 2018.
is an intracellular protozoan parasite that causes endemic tropical disease visceral leishmaniasis (VL). Present drugs used against this fatal disease are facing resistance and toxicity issues. Survival of leishmania inside the host cells depends on the parasite's capacity to cope up with highly oxidative environment. Base excision repair (BER) pathway in remains unexplored. We studied uracil DNA glycosylase (UNG), the key enzyme involved in BER pathway, and found that the glycosylase activity of recombinant LdUNG ( UNG) expressed in is in sync with the activity of the parasite lysate under different reaction conditions. Overexpression of UNG in the parasite enhances its tolerance towards various agents which produce reactive oxygen species (ROS) and shows a higher infectivity in macrophages. Surprisingly, exposure of parasite to amphotericin B and sodium antimony gluconate upregulates the expression of UNG. Further, we found that the drug resistant parasites isolated from VL patients show higher expression of UNG. Mechanisms of action of some currently used drugs include accumulation of ROS. Our findings strongly suggest that targeting LdUNG would be an attractive therapeutic strategy as well as potential measure to tackle the problem of drug resistance in the treatment of leishmaniasis.
利什曼原虫是一种细胞内原生动物寄生虫，可引起地方性热带疾病内脏利什曼病（VL）。目前用于治疗这种致命疾病的药物面临耐药性和毒性问题。利什曼原虫在宿主细胞内的存活取决于寄生虫应对高度氧化环境的能力。的碱基切除修复（BER）途径仍未得到探索。我们研究了尿嘧啶 DNA 糖基化酶（UNG），这是 BER 途径中涉及的关键酶，发现重组 LdUNG（UNG）在中的糖苷酶活性与寄生虫裂解物在不同反应条件下的活性同步。在寄生虫中过表达 UNG 可提高其对各种产生活性氧（ROS）的物质的耐受性，并在巨噬细胞中表现出更高的感染力。令人惊讶的是，暴露于两性霉素 B 和葡萄糖酸锑钠会使寄生虫中 UNG 的表达上调。此外，我们发现从 VL 患者中分离出的耐药寄生虫显示出更高的 UNG 表达。一些目前使用的药物的作用机制包括 ROS 的积累。我们的研究结果强烈表明，针对 LdUNG 将是一种有吸引力的治疗策略，也是解决抗利什曼病治疗中耐药问题的潜在措施。
