title: Lack of correlation between in vitro susceptibility to Benznidazole and phylogenetic diversity of Trypanosoma cruzi, the agent of Chagas disease.
abstract: Chagas disease remains an important health problem in Central and South America. Nitroimidazole derivative drugs like Benznidazole are commonly used to treat Trypanosoma cruzi infection. Natural variation of drug susceptibility between various T. cruzi stocks has been proposed as a possible explanation of treatment failure. Thus, the aim of this work was to determine potential correlations between in vitro Benznidazole susceptibility of different T. cruzi stocks and their genetic diversity. For this purpose, 16 natural stocks representing the overall genetic diversity of the parasite were analysed. Genetic characterisation was assessed by both random amplified polymorphic DNA (RAPD) and multilocus enzyme electrophoresis (MLEE) analyses. Drug activity was determined by two complementary methods, the MTT-PMS micro-method and FACs analysis. The 50% inhibitory concentrations (IC(50)s) were determined. Important variation of IC(50) values (7.3-16.9 microM) among stocks belonging to different discrete typing units (DTUs) was recorded. Further, correlation analysis showed that natural susceptibility to Benznidazole in T. cruzi expressed as IC(50) level was not related with its genetic structure represented by the different DTUs. These results are discussed in relation with the proposed hypothesis establishing a link between genetic diversity and biological behaviour in T. cruzi.
authors.affiliation: Génétique et Evolution des Maladies Infectieuses G.E.M.I (Ex-CEPM) UMR No. 2724 CNRS/IRD, UR 165 IRD, Centre de Recherche IRD, 911 avenue Agropolis, BP 64501, 34394 Montpellier Cedex 5, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Villarreal
authors.forename: Christian
authors.initials: C
authors.lastname: Barnabé
authors.forename: Denis
authors.initials: D
authors.lastname: Sereno
authors.forename: Michel
authors.initials: M
authors.lastname: Tibayrenc
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D004588:Electrophoresis, Cellulose Acetate; D005434:Flow Cytometry; D014644:Genetic Variation; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics; D009593:Nitroimidazoles / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010802:Phylogeny; D019105:Random Amplified Polymorphic DNA Technique; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000145:classification* / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D007527:Isoenzymes; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole