Nitazoxanide: Nematicidal mode of action and drug combination studies

Abstract

Intestinal nematodes or roundworms (aka soil-transmitted helminths or STHs) cause great disease. They infect upwards of two billion people, leading to high morbidity and a range of health problems, especially in infected children and pregnant women. Development of resistance to the two main classes of drugs used to treat intestinal nematode infections of humans has been reported. To fight STH infections, we need new and more effective drugs and ways to improve the efficacy of the old drugs. One promising alternative drug is nitazoxanide (NTZ). NTZ, approved for treating human protozoan infections, was serendipitously shown to have therapeutic activity against STHs. However, its mechanism of action against nematodes is not known. Using the laboratory nematode Caenorhabditis elegans, we show that NTZ acts on the nematodes through avr-14, an alpha-type subunit of a glutamate-gated chloride ion channel known for its role in ivermectin susceptibility. In addition, a forward genetic screen to select C. elegans mutants resistant to NTZ resulted in isolation of two NTZ resistant mutants that are not in avr-14, suggesting that additional mechanisms are involved in resistance to NTZ. We found that NTZ combines synergistically with other classes of anthelmintic drugs, i.e. albendazole and pyrantel, making it a good candidate for further studies on its use in drug combination therapy of STH infections. Given NTZ acts against a wide range of nematode parasites, our findings also validate avr-14 as an excellent target for pan-STH therapy.

Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis

“…21,22 We envisioned that compounds 1-8 could act as potential GiFBPA inhibitors, due to the multifactorial mode of action and the reports of new drug targets for Nitazoxanide. 10 compound screen to identify inhibitors of GiFBPA was performed.…”

“…The mode of action of Nitazoxanide is multifactorial, but the most accepted mechanism is by noncompetitive inhibition of the pyruvate:ferredoxin/flavodoxin oxidoreductases (PFORs). 10 Alternative mechanisms of action of Nitazoxanide are inhibition of protein disulfide isomerase 11 and interaction with Giardia lamblia nitroreductases (GlNR1, GlNR2). 10,12,13 In an effort to improve the antiprotozoal activity of NTZ, we envisioned several modifications in the central core, as well as the aromatic side chain.…”

“…10 Alternative mechanisms of action of Nitazoxanide are inhibition of protein disulfide isomerase 11 and interaction with Giardia lamblia nitroreductases (GlNR1, GlNR2). 10,12,13 In an effort to improve the antiprotozoal activity of NTZ, we envisioned several modifications in the central core, as well as the aromatic side chain. The in vitro antiparasitic activities of these new compounds on intestinal unicellular parasite (Giardia intestinalis), a urogenital tract parasite (Trichomonas vaginalis), and the potential cytotoxicity over VERO cell line are reported in this work.…”

Pharmacological Treatment of Giardiasis

“…In the case of protozoa, electron and biochemical resonance studies have shown that pyruvate ferridoxin oxidoreductase (PFOR) and, to a lesser extent, hydrogenase reduce ferredoxin, which is oxidized by the nitro group in position 5 over the nitroheterocyclic compounds such as nitazoxanide [39]. In these organisms, nitazoxanide is reduced to a toxic radical in an organelle of carbohydrate metabolism and the hydrogenosome which contains hydrogenase PFOR and ferredoxin [13,15,43].…”

Comparative evaluation of anthelmintic and antibacterial activities in leaves and fruits of Garcinia cambogia (Gaertn.) desr. and Garcinia indica (Dupetit-Thouars) choisy

“…In human beings, they cause mal-absorption, diarrhea, anaemia and other intestinal problems (Kumar et al 2012). More than two billion people are infected with different intestinal worms worldwide (Somvanshi et al 2014). The nematode infections are more prevalent in developing countries due to poor sanitation and hygiene (Dhar et al 1982).…”