Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi
| Autor: | Oliver C.F. Orban, Conrad Kunick, Natalia Sasoni, Nisha Jain Garg, Diego Gustavo Arias, Carlos Robello, M. Paola Zago, Andrea C. Mesías, Marcelo A. Comini, Cecilia Pérez Brandán |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Chagas Cardiomyopathy
0301 basic medicine Drug Resistance Protozoan Proteins Trypanothione Pharmacology medicine.disease_cause Biochemistry Antioxidants purl.org/becyt/ford/1 [https] chemistry.chemical_compound 0302 clinical medicine Transgenes Cells Cultured media_common biology Bioquímica y Biología Molecular Benznidazole Oxidation-Reduction CIENCIAS NATURALES Y EXACTAS medicine.drug Drug Chagas disease Combination therapy Trypanosoma cruzi media_common.quotation_subject TRYPANOTHIONE SYNTHETASE Antiprotozoal Agents Article ANTI-PARASITE DRUGS PAULLONES Ciencias Biológicas 03 medical and health sciences Amide Synthases Physiology (medical) medicine Animals Humans purl.org/becyt/ford/1.6 [https] Nifurtimox Cell Proliferation CHAGAS DISEASE TRYPANOSOMA CRUZI biology.organism_classification medicine.disease Oxidative Stress 030104 developmental biology chemistry SMALL MOLECULE INHIBITORS 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | Background: Chagas cardiomyopathy, caused by Trypanosoma cruzi infection, continues to be a neglected illness, and has a major impact on global health. The parasite undergoes several stages of morphological and biochemical changes during its life cycle, and utilizes an elaborated antioxidant network to overcome the oxidants barrier and establish infection in vector and mammalian hosts. Trypanothione synthetase (TryS) catalyzes the biosynthesis of glutathione-spermidine adduct trypanothione (T(SH)2) that is the principal intracellular thiol-redox metabolite in trypanosomatids. Methods and Results: We utilized genetic overexpression (TryShi) and pharmacological inhibition approaches to examine the role of TryS in T. cruzi proliferation, tolerance to oxidative stress and resistance to anti-protozoal drugs. Our data showed the expression and activity of TryS was increased in all morphological stages of TryShi (vs. control) parasites. In comparison to controls, the TryShi epimastigotes (insect stage) recorded shorter doubling time, and both epimastigotes and infective trypomastigotes of TryShi exhibited 36-71% higher resistance to H2O2 (50-1000 M) and heavy metal (1-500 M) toxicity. Treatment with TryS inhibitors (5-30 M) abolished the proliferation and survival advantages against H2O2 pressure in a dose-dependent manner in both TryShi and control parasites. Further, epimastigote and trypomastigote forms of TryShi (vs. control) T. cruzi tolerated higher doses of benznidazole and nifurtimox, the drugs currently administered for acute Chagas disease treatment. Conclusions: TryS is essential for proliferation and survival of T. cruzi under normal and oxidant stress conditions, and provides an advantage to the parasite to develop resistance against currently used antitrypanosomal drugs. TryS indispensability has been chemically validated with inhibitors that may be useful for drug combination therapy against Chagas disease. Fil: Mesias, Andrea Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Sasoni, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; Argentina Fil: Arias, Diego Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; Argentina Fil: Pérez Brandan, Cecilia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Orban, Oliver C. F.. Technische Universitat Carolo Wilhelmina Zu Braunschweig.; Alemania Fil: Kunick, Conrad. Technische Universitat Carolo Wilhelmina Zu Braunschweig.; Alemania Fil: Robello, Carlos. Instituto Pasteur de Montevideo; Uruguay Fil: Comini, Marcelo. Instituto Pasteur de Montevideo; Uruguay Fil: Garg, Nisha J.. University of Texas Medical Branch; Estados Unidos Fil: Zago, María Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina |
| Databáze: | OpenAIRE |
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