title: Effects of metronidazole analogues on Giardia lamblia: experimental infection and cell organization.
abstract: The chemotherapeutic agents used for the treatment of giardiasis are often associated with adverse side effects and are refractory cases, due to the development of resistant parasites. Therefore the search for new drugs is required. We have previously reported the giardicidal effects of metronidazole (MTZ) and its analogues (MTZ-Ms, MTZ-Br, MTZ-N(3), and MTZ-I) on the trophozoites of Giardia lamblia. Now we evaluated the activity of some giardicidal MTZ analogues in experimental infections in gerbils and its effects on the morphology and ultrastructural organization of Giardia. The giardicidal activity in experimental infections showed ED(50) values significantly lower for MTZ-I and MTZ-Br when compared to MTZ. Transmission electron microscopy was employed to approach the mechanism(s) of action of MTZ analogues upon the protozoan. MTZ analogues were more active than MTZ in changing significantly the morphology and ultrastructure of the parasite. The analogues affected parasite cell vesicle trafficking, autophagy, and triggered differentiation into cysts. These results coupled with the excellent giardicidal activity and lower toxicity demonstrate that these nitroimidazole derivates may be important therapeutic alternatives for combating giardiasis. In addition, our results suggest a therapeutic advantage in obtaining synthetic metronidazole analogues for screening of activities against other infectious agents.
authors: Depto. Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, Brazil.
authors: Haendel G N O
authors: HG
authors: Busatti
authors: Ricardo J
authors: RJ
authors: Alves
authors: Karla G
authors: KG
authors: Santana-Anjos
authors: Frederico F
authors: FF
authors: Gil
authors: Marcia C
authors: MC
authors: Cury
authors: Marcos A
authors: MA
authors: Vannier-Santos
authors: Maria A
authors: MA
authors: Gomes
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D005849:Gerbillinae; D016829:Giardia lamblia / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D005873:Giardiasis / Q000469:parasitology*; D020128:Inhibitory Concentration 50; D008795:Metronidazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D059208:Parasite Load; D053058:Trophozoites / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D000981:Antiprotozoal Agents; D008795:Metronidazole