Proteomic and ultrastructural analysis of the effect of a new nitazoxanide-N-methyl-1H-benzimidazole hybrid against Giardia intestinalis
Por:
Matadamas-Martinez, Felix, Castillo, Rafael, Hernandez-Campos, Alicia, Mendez-Cuesta, Carlos, de Souza, Wanderley, Gadelha, Ana Paula, Nogueda-Torres, Benjamin, Manuel Hernandez, Jose, Yepez-Mulia, Lilian
Publicada:
1 abr 2016
Categoría:
Veterinary (miscellaneous)
Resumen:
In an effort to develop alternative drugs for the treatment of
giardiasis our research group has synthesized and evaluated a novel
nitazoxanide and N-methyl-IH-benzimidazole hybrid molecule, named
CMC-20. It showed an IC50 of 0.010 mu M on Giardia intestinalis, lower
than the IC50 values of 0.015, 0.037 and 1.224 mu M for nitazoxanide,
albendazole and metronidazole, respectively. In addition, we report
studies carried out on its mechanism of action and effect at the
ultrastructural level on G. intestinalis. The proteomic analysis of
trophozoites treated with CMC-20 revealed significant changes in the
expression level of proteins of the cytoskeleton, alpha and beta
tubulin, alpha-1, beta giardin and axoneme-associated protein, among
other molecules. Ultra structural studies demonstrated that CMC-20
induces morphological changes on the parasite that loses its
characteristic pear shape. Uncommon large bulbous structure at the
flagella end, and parasites showing flange membrane bending and a
concave depression in the ventral region, resembling an encystation
process, were also observed. In addition, some apoptotic and
autophagic-like features, such as membrane blebbing, intense
vacuolation, chromatin condensation and multilamellar bodies were
detected. Phosphatidylserine externalization was determined as an
apoptotic marker by flow cytometry and immunofluorescence microscopy;
however, a typical ladder-like DNA fragmentation profile was not
detected. Although it was found that CMC-20 triggers the encystation
process, damage to the cyst wall indicates loss of viability. (C) 2016
Elsevier Ltd. All rights reserved.
Filiaciones:
Matadamas-Martinez, Felix:
Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Dept Parasitol, Mexico City 11340, DF, Mexico
Castillo, Rafael:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
Hernandez-Campos, Alicia:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
Mendez-Cuesta, Carlos:
Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico
de Souza, Wanderley:
Univ Fed Rio de Janeiro, Lab Ultraestrutura Celular Hertha Meyer, Inst Biofis Carlos Chagas Filho, BR-21949900 Rio de Janeiro, Brazil
Inst Nacl Metrol Qualidade & Tecnol, Metrol Aplicada Ciencias Vida, Rio De Janeiro, Brazil
Gadelha, Ana Paula:
Univ Fed Rio de Janeiro, Lab Ultraestrutura Celular Hertha Meyer, Inst Biofis Carlos Chagas Filho, BR-21949900 Rio de Janeiro, Brazil
Inst Nacl Metrol Qualidade & Tecnol, Metrol Aplicada Ciencias Vida, Rio De Janeiro, Brazil
Nogueda-Torres, Benjamin:
Inst Politecn Nacl, Escuela Nacl Ciencias Biol, Dept Parasitol, Mexico City 11340, DF, Mexico
Manuel Hernandez, Jose:
Ctr Invest & Estudios Avanzados IPN, Dept Biol Celular, Mexico City 07360, DF, Mexico
Yepez-Mulia, Lilian:
Pediat Inst Mexicano Seguro Social, Unidad Invest Med Enfermedades Infecciosas & Para, Mexico City 06720, DF, Mexico
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