Deletion of copies of the gene encoding old yellow enzyme (TcOYE), a NAD(P)H flavin oxidoreductase, associates with in vitro-induced benznidazole resistance in Trypanosoma cruzi

Murta, Silvane Maria Fonseca; Krieger, Marco Aurélio; Montenegro, Luciana Ribeiro; Campos, Fernanda Fraga; Probst, Christian M.; Ávila, Andréa Rodrigues; Muto, Nair Hideko; Oliveira, Regina C. de; Nunes, Luiz R.; Nirdé, Philippe; Bruna-Romero, Oscar; Goldenberg, Samuel; Romanha, Álvaro J.

doi:10.1016/j.molbiopara.2005.12.001

Cited by 78 publications

(103 citation statements)

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“…66 Many molecular studies have compared those two populations to identify resistance markers. [67][68][69] Although no correlation was detected, other studies have found differences in the in vitroinduced BZ-resistant strains (17WTS X 17LER). 67 More recently, a proteomic analysis of BZS-Y/BZR-Y and 17WTS/ 17LER also identified many overexpressed proteins in the BZR-Y population.…”

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confidence: 82%

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares¹,

Torrecilhas²,

Assis³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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confidence: 82%

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Soares¹,

Torrecilhas²,

Assis³

et al. 2012

The American Society of Tropical Medicine and Hygiene

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“…Their use is complicated by the distinct susceptibility of different parasite strains ( (Filardi and Brener, 1987). Probably, this is due to diverse mechanisms including differences in the free thiol content of the parasite, deletion of copies of the 'old yellow enzyme' gene (Murta et al, 2006) or type I nitroreductase (NTR) downregulation in trypanosomes (Wilkinson et al, 2008).…”

Section: Treatment Of Chagas Diseasementioning

confidence: 99%

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

et al. 2010

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There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20%-30% of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown.

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“…En este sentido, al ser justo las cepas más resistentes, aisladas de aquellas regiones donde posiblemente no se ha suministrado el tratamiento, se infiere que las cepas colombianas de T. cruzi podrían poseer resistencia natural al benzonidazol que no depende del uso de los medicamentos, que pueden generar procesos de inducción de resistencia. Por lo tanto, sugerimosEn la actualidad, diversos autores han tratado de correlacionar los mecanismos de resistencia natural con los de resistencia inducida (16)(17)(18)(19)(20)(21). Sin embargo, hasta el momento no se han encontrado patrones de expresión similares en cepas que presentan los dos tipos de resistencia, lo que ha llevado a concluir que diferentes mecanismos actúan en ambos tipos de resistencia.…”

Section: Discussionunclassified

“…Además, se reportó que es posible inducir resistencia en este parásito, tanto in vitro como in vivo, por presiones continuas con estos medicamentos (12)(13)(14)(15), lo cual genera poblaciones resistentes a concentraciones de benzonidazol de hasta 220 μM (15), y se han propuesto algunos genes involucrados en el surgimiento del fenotipo de resistencia a este medicamento (12,13,(16)(17)(18)(19)(20)(21). A la fecha, no se han podido correlacionar los mecanismos moleculares involucrados entre estos dos tipos de resistencia (16)(17)(18)(19)(20)(21), ni tampoco la resistencia con otros parámetros biológicos, genéticos o bioquímicos de T. cruzi (22,23).…”

Section: Sensibilidad Al Benzonidazol De Trypanosoma Cruziunclassified

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

Mejía-Jaramillo¹,

Fernández²,

Montilla³

et al. 2012

biomedica

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Introducción. La enfermedad de Chagas, causada por Trypanosoma cruzi, es uno de los problemas más graves de salud pública en el continente americano. El benzonidazol es uno de los dos medicamentos utilizados para tratar la enfermedad de Chagas. Sin embargo, la variación de la sensibilidad del parásito a este medicamento es una de las principales causas del fracaso del tratamiento. Objetivo. Evaluar la sensibilidad in vitro al benzonidazol de cepas colombianas de T. cruzi de diferentes orígenes y procedencia geográfica. Materiales y métodos. Treinta y tres cepas colombianas de T. cruzi aisladas de humanos, vectores y mamíferos, se analizaron in vitro mediante el micrométodo enzimático de MTT para determinar la concentración inhibitoria 50 (CI 50 ) al benzonidazol. Se estudió la correlación entre la sensibilidad in vitro al medicamento y diferentes parámetros biológicos y eco-epidemiológicos. Resultados. El análisis de sensibilidad al medicamento indicó que el 36 % de las cepas eran sensibles, el 48 %, parcialmente resistentes y, el 16 %, resistentes al benzonidazol. Los análisis de correlación entre las CI 50 con algunos parámetros biológicos y eco-epidemiológicos, mostraron diferencias en cuanto a la sensibilidad según el origen biológico y el área geográfica de procedencia de la cepa. Conclusiones. Existe una gran variabilidad en cuanto a la sensibilidad al benzonidazol de las cepas circulantes de T. cruzi en Colombia, lo cual sugiere la presencia de cepas naturalmente resistentes en el país. Palabras clave:Trypanosoma cruzi, enfermedad de Chagas/terapia, inmunidad innata, Colombia. Trypanosoma cruzi strains resistant to benznidazole occurring in ColombiaIntroduction. Chagas disease caused by Trypanosoma cruzi is one of the most serious public health problems in the Americas. Benznidazole is one of two drugs used to treat Chagas' disease. However, the variation in susceptibility of the parasite to this drug is one of the main causes of treatment failure. Objective. The in vitro susceptibility to benznidazole was assessed in Colombian strains of T. cruzi from several sources and geographical regions. Materials and methods. Thirty-three Colombian T. cruzi strains were isolated from humans, vectors and mammals. These were analyzed in vitro by the MTT enzymatic micromethod to determine the IC 50 to benznidazole. Additionally, the in vitro susceptibility was correlated with several biological and ecoepidemiological parameters. Results. Thirty-six percent of the strains were considered to be sensitive, 48% partially resistant, and 16% were resistant. Correlations between the IC 50 and several biological and eco-epidemiological parameters indicated that differences in susceptibility depended on the biological source and geographical origin of the strain. Conclusions. A high degree of variability exists in the susceptibility to benznidazole of T. cruzi strains in Colombia. The distribution data indicate the presence and circulation of naturally resistant strains.

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Deletion of copies of the gene encoding old yellow enzyme (TcOYE), a NAD(P)H flavin oxidoreductase, associates with in vitro-induced benznidazole resistance in Trypanosoma cruzi

Cited by 78 publications

References 49 publications

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Intraspecies Variation in Trypanosoma cruzi GPI-Mucins: Biological Activities and Differential Expression of α-Galactosyl Residues

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

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