Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi

Andrea C. Mesías, Natalia Sasoni, Diego G. Arias, Cecilia Pérez Brandán, Oliver C.F. Orban, Conrad Kunick, Carlos Robello, Marcelo A. Comini, Nisha Garg, M. Paola Zago

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    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 μM) and heavy metal (1–500 μM) toxicity. Treatment with TryS inhibitors (5–30 μM) 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 anti-trypanosomal drugs. TryS indispensability has been chemically validated with inhibitors that may be useful for drug combination therapy against Chagas disease.

    Original languageEnglish (US)
    Pages (from-to)23-34
    Number of pages12
    JournalFree Radical Biology and Medicine
    Volume130
    DOIs
    StatePublished - Jan 1 2019

    Fingerprint

    trypanothione synthetase
    Trypanosoma cruzi
    Growth
    Pharmaceutical Preparations
    Communicable Disease Control
    Chagas Disease
    Oxidants
    Parasites
    Chagas Cardiomyopathy
    Nifurtimox
    Drug therapy
    Oxidative stress
    Spermidine
    Biosynthesis
    Acute Disease
    Drug Combinations
    Metabolites
    Heavy Metals
    Infection
    Combination Drug Therapy

    Keywords

    • Anti-parasite drugs
    • Chagas disease
    • Paullones
    • Small molecule inhibitors
    • Trypanosoma cruzi
    • Trypanothione synthetase

    ASJC Scopus subject areas

    • Biochemistry
    • Physiology (medical)

    Cite this

    Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi. / Mesías, Andrea C.; Sasoni, Natalia; Arias, Diego G.; Pérez Brandán, Cecilia; Orban, Oliver C.F.; Kunick, Conrad; Robello, Carlos; Comini, Marcelo A.; Garg, Nisha; Zago, M. Paola.

    In: Free Radical Biology and Medicine, Vol. 130, 01.01.2019, p. 23-34.

    Research output: Contribution to journalArticle

    Mesías, AC, Sasoni, N, Arias, DG, Pérez Brandán, C, Orban, OCF, Kunick, C, Robello, C, Comini, MA, Garg, N & Zago, MP 2019, 'Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi', Free Radical Biology and Medicine, vol. 130, pp. 23-34. https://doi.org/10.1016/j.freeradbiomed.2018.10.436
    Mesías, Andrea C. ; Sasoni, Natalia ; Arias, Diego G. ; Pérez Brandán, Cecilia ; Orban, Oliver C.F. ; Kunick, Conrad ; Robello, Carlos ; Comini, Marcelo A. ; Garg, Nisha ; Zago, M. Paola. / Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi. In: Free Radical Biology and Medicine. 2019 ; Vol. 130. pp. 23-34.
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    T1 - Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi

    AU - Mesías, Andrea C.

    AU - Sasoni, Natalia

    AU - Arias, Diego G.

    AU - Pérez Brandán, Cecilia

    AU - Orban, Oliver C.F.

    AU - Kunick, Conrad

    AU - Robello, Carlos

    AU - Comini, Marcelo A.

    AU - Garg, Nisha

    AU - Zago, M. Paola

    PY - 2019/1/1

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    N2 - 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 μM) and heavy metal (1–500 μM) toxicity. Treatment with TryS inhibitors (5–30 μM) 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 anti-trypanosomal drugs. TryS indispensability has been chemically validated with inhibitors that may be useful for drug combination therapy against Chagas disease.

    AB - 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 μM) and heavy metal (1–500 μM) toxicity. Treatment with TryS inhibitors (5–30 μM) 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 anti-trypanosomal drugs. TryS indispensability has been chemically validated with inhibitors that may be useful for drug combination therapy against Chagas disease.

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