Differential gene expression in Trypanosoma cruzi populations susceptible and resistant to benznidazole

Murta, Silvane Maria Fonseca; Nogueira, Fernanda B.; Santos, Paula Fernandes dos; Campos, Fernanda Magalhães Freire; Volpe, C.P.; Liarte, Daniel Barbosa; Nirdé, Philippe; Probst, Christian M.; Krieger, Marco Aurélio; Goldenberg, Samuel; Romanha, Álvaro J.

doi:10.1016/j.actatropica.2008.04.011

Cited by 34 publications

(32 citation statements)

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“…Approaches to understand the Bz mechanism of action have yielded a wide range of proteins (14,15,16,22,29), but regulation of neither NTR I nor TcAKR has been detected. There is no documentation regarding Bz detoxification pathways, and no enzymes have so far been demonstrated to be involved in this mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…However, evidence indicates that although Bz is reduced to its anion radical, redox cycling may not be relevant for its mode of action, as is the case with Nx (8,10,11,12,13). Moreover, cells selected for Bz resistance display altered expression levels of several additional enzymes, indicating that other components of the parasite are involved (14,15,16). It has been proposed that Bz activity is mediated via highly toxic reduced intermediates that covalently bind macromolecules and cause deleterious effects, including DNA damage and thiol depletion (8,17,18).…”

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confidence: 99%

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Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Garavaglia

Laverrière

Cannata

et al. 2016

Antimicrob Agents Chemother

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b Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC 50 ) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH-and NADH-dependent reductases.C hagas' disease, caused by the protozoan Trypanosoma cruzi, affects 11 million people in Latin America (1). The parasite is usually transmitted to humans and other mammals by triatomine bugs. However, transmission can also be oral (through contaminated food), congenital, or transfusional or by organ transplantation, even in countries where the disease is not endemic (2). The course of infection includes an acute phase followed by an indeterminate phase without symptoms, which lasts throughout life in most infected people. Approximately 30% of patients can develop a chronic phase characterized by cardiac and/or digestive pathologies that can lead to death (3).Benznidazole (Bz) and, to a lesser extent, nifurtimox (Nx) are the drugs currently used for treatment of T. cruzi infection (4). Although the mechanism of action of these nitroheterocyclic compounds is not clearly understood, it is known that, to exert their trypanocidal effects, they need to be activated through the reduction of their nitro group (5). Several studies have proposed that an NADH-dependent trypanosomal type I nitroreductase (NTR I) is a key enzyme which catalyzes Bz and Nx activation in vivo (6,7,8,9). However, evidence indicates that although Bz is reduced to its anion radical, redox cycling may not be relevant for its mode of action, as ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Garavaglia

Laverrière

Cannata

et al. 2016

Antimicrob Agents Chemother

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“…The parasite's biological properties play an important role in the disease pathogenesis (morbidity) and may affect drug efficacy (Andrade et al 1975, Tibayrenc et al 1986, Andrade & Magalhães 1996, Revollo et al 1998, Toledo et al 2003. The occurrence of naturally resistant T. cruzi strains demonstrated in experimental models (Filardi & Brener 1987, Murta et al 2008) is supposed to be one of the most important factors explaining the low rates of cure in some treated chagasic patients from endemic zones, as seen in Central Brazil in patients infected with strains of the biodeme type III, Z1 (T. cruzi I) as compared with those infected with biodeme II, Z2 (T. cruzi II) (Andrade et al 1992). In fact, the occurrence of predominant strains exhibiting different susceptibility levels (in specific geographic areas) has been associated with a high variability of clinical symptoms concerning treated patients.…”

Section: Heterogeneity Of T Cruzi Populationsmentioning

confidence: 99%

Usefulness of PCR-based assays to assess drug efficacy in Chagas disease chemotherapy: value and limitations

Britto¹

2009

Mem. Inst. Oswaldo Cruz

102

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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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Differential gene expression in Trypanosoma cruzi populations susceptible and resistant to benznidazole

Cited by 34 publications

References 35 publications

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism

Usefulness of PCR-based assays to assess drug efficacy in Chagas disease chemotherapy: value and limitations

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

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