Characterisation of the in vitro activity of a Nitazoxanide-N-methyl-1H-benzimidazole hybrid molecule against albendazole and nitazoxanide susceptible and resistant strains of Giardia intestinalis and its in vivo giardicidal activity

Abstract

BACKGROUND It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20 showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.

Anti-GiardiaDrug Discovery: Current Status and Gut Feelings

“…With an impressive IC 50 of 10–71 nM , (Table ). CMC-20, a nitazoxanide-benzimidazole hybrid, shows promising, although reduced activity against both benzimidazole- and nitazoxanide-resistant parasite lines . However, the in vivo activity of CMC-20 has not yet been reported.…”

“…This compound, CMC-20, is arguably the most attractive double pharmacophore anti- Giardia hybrid compound identified to date. With an impressive IC 50 of 10–71 nM , (Table ). CMC-20, a nitazoxanide-benzimidazole hybrid, shows promising, although reduced activity against both benzimidazole- and nitazoxanide-resistant parasite lines .…”

“…CMC-20, a nitazoxanide-benzimidazole hybrid, shows promising, although reduced activity against both benzimidazole-and nitazoxanide- resistant parasite lines. 200 However, the in vivo activity of CMC-20 has not yet been reported. Beyond dual anti-Giardia pharmacophore hybrid compounds, nonsteroidal anti-inflammatory drugs (NSAID) have been hybridized with nitazoxanide as a mechanism to improve compound activity.…”

Antimicrobial resistance of the enteric protozoon Giardia duodenalis – A narrative review

“…As a comparatively new approach, hybrid compounds created by combining different giardicidal drugs within one molecule have been introduced [ 119 ]. For example, CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, showed giardicidal effects in G. duodenalis strains resistant against albendazole or nitazoxanide alone by affecting the parasite’s microtubule reservoir, triggering the parasite’s encystation and alpha-7.2 giardin co-localization with CWP-1 protein in vitro and in the murine model [ 120 ].…”