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

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.

LanguageEnglish (US)
Pages23-34
Number of pages12
JournalFree Radical Biology and Medicine
Volume130
DOIs
StatePublished - Jan 1 2019

Fingerprint

trypanothione synthetase
Chagas Disease
Trypanosoma cruzi
Growth
Pharmaceutical Preparations
Communicable Disease Control
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.
@article{106848b3b8c94615b1a060e028fc70b8,
title = "Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi",
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.",
keywords = "Anti-parasite drugs, Chagas disease, Paullones, Small molecule inhibitors, Trypanosoma cruzi, Trypanothione synthetase",
author = "Mes{\'i}as, {Andrea C.} and Natalia Sasoni and Arias, {Diego G.} and {P{\'e}rez Brand{\'a}n}, Cecilia and Orban, {Oliver C.F.} and Conrad Kunick and Carlos Robello and Comini, {Marcelo A.} and Nisha Garg and Zago, {M. Paola}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.freeradbiomed.2018.10.436",
language = "English (US)",
volume = "130",
pages = "23--34",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

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

Y1 - 2019/1/1

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.

KW - Anti-parasite drugs

KW - Chagas disease

KW - Paullones

KW - Small molecule inhibitors

KW - Trypanosoma cruzi

KW - Trypanothione synthetase

UR - http://www.scopus.com/inward/record.url?scp=85055680903&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055680903&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2018.10.436

DO - 10.1016/j.freeradbiomed.2018.10.436

M3 - Article

VL - 130

SP - 23

EP - 34

JO - Free Radical Biology and Medicine

T2 - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -