Shakya Anshul, Bhat Hans Raj, Ghosh Surajit Kumar
Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India.
Curr Drug Discov Technol. 2018;15(3):201-213. doi: 10.2174/1570163814666170727130003.
The thiazolide nitazoxanide (NTZ) is a broad-spectrum antiinfective drug that adversely affects viability, growth, and proliferation of a range of extracellular and intracellular protozoan, helminths, anaerobic and microaerophilic bacteria, and viruses.
Current review compiled the potential chemotherapeutic efficacy of NTZ against a variety of such disease-causing macro and/or micro-organisms as well as neoplastic cells, using various search engines viz. Web of Science, Scopus and Pub- Med up to February 2017.
The most accepted anti-infective mechanism of NTZ involves impairment of the energy metabolism in anaerobic pathogens by inhibition of the pyruvate: ferredoxin/ flavodoxin oxidoreductase (PFOR). In parasitic-protozoan NTZ also induces lesions/voids in the cell membrane and depolarises the mitochondrial membrane along with the inhibition of quinone oxidoreductase NQO1, nitroreductase-1 and protein disulphide isomerase. NTZ also inhibits the glutathione-S-transferase (a major detoxifying enzyme) and modulates a gene (avr-14 gene) encoding for the alphatype subunit of glutamate-gated chloride ion channel present in the nematodes. Apart from well recognized non-competitive inhibition of the PFOR in anaerobic bacteria, NTZ also showed a variety of other antibacterial mechanisms viz. inhibits pyruvate dehydrogenase in the Escherichia coli, disrupts the membrane potential and pH homeostasis in the Mycobacterium tuberculosis, suppresses the chaperone/usher (CU) pathway of the gram-negative bacteria and stimulates host macrophage autophagy in the tubercular patients. NTZ also suppresses the viral replication by inhibiting maturation of the viral hemagglutinin and the viral transcription factor immediate early 2 (IE2) as well as by activating the eukaryotic translation initiation factor 2α (an antiviral intracellular protein). Additionally, NTZ expresses inhibitory effect on the tumour cell progression by modulating drug detoxification (glutathione-S-transferase P1), unfolded protein response, autophagy, anti-cytokines activities and c-Myc inhibition.
These potentially versatile molecular interactions of NTZ within invading pathogen(s) and immunomodulatory efficacy over the hosts, justify the multifunctional chemotherapeutic significance of this chemical agent.
噻唑酰胺硝唑尼特（NTZ）是一种广谱抗感染药物，对多种细胞外和细胞内原生动物、蠕虫、厌氧和微需氧细菌以及病毒的活力、生长和增殖具有不利影响。
本综述利用各种搜索引擎，即科学网、Scopus和PubMed，检索截至2017年2月NTZ对各种致病的宏观和/或微生物以及肿瘤细胞的潜在化疗效果。
NTZ最被认可的抗感染机制包括通过抑制丙酮酸：铁氧化还原蛋白/黄素氧化还原蛋白氧化还原酶（PFOR）来损害厌氧病原体的能量代谢。在寄生原生动物中，NTZ还会诱导细胞膜出现损伤/空洞，使线粒体膜去极化，同时抑制醌氧化还原酶NQO1、硝基还原酶-1和蛋白质二硫键异构酶。NTZ还抑制谷胱甘肽-S-转移酶（一种主要的解毒酶），并调节线虫中编码谷氨酸门控氯离子通道α亚基的基因（avr-14基因）。除了在厌氧细菌中对PFOR有公认的非竞争性抑制作用外，NTZ还表现出多种其他抗菌机制，即抑制大肠杆菌中的丙酮酸脱氢酶，破坏结核分枝杆菌的膜电位和pH稳态，抑制革兰氏阴性菌的伴侣/外膜蛋白（CU）途径，并刺激结核病患者的宿主巨噬细胞自噬。NTZ还通过抑制病毒血凝素的成熟和病毒转录因子立即早期2（IE2）以及激活真核翻译起始因子2α（一种抗病毒细胞内蛋白）来抑制病毒复制。此外，NTZ通过调节药物解毒（谷胱甘肽-S-转移酶P1）、未折叠蛋白反应、自噬、抗细胞因子活性和c-Myc抑制来表达对肿瘤细胞进展的抑制作用。
NTZ在入侵病原体中的这些潜在的多用途分子相互作用以及对宿主的免疫调节功效，证明了这种化学药剂的多功能化疗意义。
