The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi
Chagas disease, which is caused by Trypanosoma cruzi, establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people wo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2021.617504/full |
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| author | Carolina Machado Macedo Francis Monique de Souza Saraiva Jéssica Isis Oliveira Paula Suelen de Brito Nascimento Suelen de Brito Nascimento Débora de Souza dos Santos Costa Paulo Roberto Ribeiro Costa Ayres Guimarães Dias Marcia Cristina Paes Marcia Cristina Paes Natália Pereira Nogueira Natália Pereira Nogueira |
| author_facet | Carolina Machado Macedo Francis Monique de Souza Saraiva Jéssica Isis Oliveira Paula Suelen de Brito Nascimento Suelen de Brito Nascimento Débora de Souza dos Santos Costa Paulo Roberto Ribeiro Costa Ayres Guimarães Dias Marcia Cristina Paes Marcia Cristina Paes Natália Pereira Nogueira Natália Pereira Nogueira |
| author_sort | Carolina Machado Macedo |
| collection | DOAJ |
| description | Chagas disease, which is caused by Trypanosoma cruzi, establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people worldwide. The scenario is even more frustrating since the main chemotherapy is based on benznidazole, a drug that presents severe side effects and low efficacy in the chronic phase of the disease. Thus, the search for new therapeutic alternatives is urgent. In the present study, we investigated the activity of a novel phenyl-tert-butyl-nitrone (PBN) derivate, LQB303, against T. cruzi. LQB303 presented trypanocidal effect against intracellular [IC50/48 h = 2.6 μM] and extracellular amastigotes [IC50/24 h = 3.3 μM] in vitro, leading to parasite lysis; however, it does not present any toxicity to host cells. Despite emerging evidence that mitochondrial metabolism is essential for amastigotes to grow inside mammalian cells, the mechanism of redox-active molecules that target T. cruzi mitochondrion is still poorly explored. Therefore, we investigated if LQB303 trypanocidal activity was related to the impairment of the mitochondrial function of amastigotes. The investigation showed there was a significant decrease compared to the baseline oxygen consumption rate (OCR) of LQB303-treated extracellular amastigotes of T. cruzi, as well as reduction of “proton leak” (the depletion of proton motive force by the inhibition of F1Fo ATP synthase) and “ETS” (maximal oxygen consumption after uncoupling) oxygen consumption rates. Interestingly, the residual respiration (“ROX”) enhanced about three times in LQB303-treated amastigotes. The spare respiratory capacity ratio (SRC: cell ability to meet new energy demands) and the ATP-linked OCR were also impaired by LQB303 treatment, correlating the trypanocidal activity of LQB303 with the impairment of mitochondrial redox metabolism of amastigotes. Flow cytometric analysis demonstrated a significant reduction of the ΔΨm of treated amastigotes. LQB303 had no significant influence on the OCR of treated mammalian cells, evidencing its specificity against T. cruzi mitochondrial metabolism. Our results suggest a promising trypanocidal activity of LQB303, associated with parasite bioenergetic inefficiency, with no influence on the host energy metabolism, a fact that may point to an attractive alternative therapy for Chagas disease. |
| first_indexed | 2024-12-20T09:56:03Z |
| format | Article |
| id | doaj.art-9759abbd9b764df59acebd09a8b83b6a |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-20T09:56:03Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-9759abbd9b764df59acebd09a8b83b6a2022-12-21T19:44:27ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-04-011210.3389/fmicb.2021.617504617504The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruziCarolina Machado Macedo0Francis Monique de Souza Saraiva1Jéssica Isis Oliveira Paula2Suelen de Brito Nascimento3Suelen de Brito Nascimento4Débora de Souza dos Santos Costa5Paulo Roberto Ribeiro Costa6Ayres Guimarães Dias7Marcia Cristina Paes8Marcia Cristina Paes9Natália Pereira Nogueira10Natália Pereira Nogueira11Laboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG – Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG – Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG – Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG – Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Hematologia, Departamento de Patologia, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro, BrazilDepartamento de Química Orgânica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Química Bioorgânica, NPPN, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilDepartamento de Química Orgânica, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilLaboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG – Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilInstituto Nacional de Ciência e Tecnologia - Entomologia Molecular (INCT-EM), Rio de Janeiro, BrazilLaboratório de Interação de Tripanossomatídeos e Vetores, Departamento de Bioquímica, IBRAG – Universidade do Estado do Rio de Janeiro, Rio de Janeiro, BrazilInstituto Nacional de Ciência e Tecnologia - Entomologia Molecular (INCT-EM), Rio de Janeiro, BrazilChagas disease, which is caused by Trypanosoma cruzi, establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people worldwide. The scenario is even more frustrating since the main chemotherapy is based on benznidazole, a drug that presents severe side effects and low efficacy in the chronic phase of the disease. Thus, the search for new therapeutic alternatives is urgent. In the present study, we investigated the activity of a novel phenyl-tert-butyl-nitrone (PBN) derivate, LQB303, against T. cruzi. LQB303 presented trypanocidal effect against intracellular [IC50/48 h = 2.6 μM] and extracellular amastigotes [IC50/24 h = 3.3 μM] in vitro, leading to parasite lysis; however, it does not present any toxicity to host cells. Despite emerging evidence that mitochondrial metabolism is essential for amastigotes to grow inside mammalian cells, the mechanism of redox-active molecules that target T. cruzi mitochondrion is still poorly explored. Therefore, we investigated if LQB303 trypanocidal activity was related to the impairment of the mitochondrial function of amastigotes. The investigation showed there was a significant decrease compared to the baseline oxygen consumption rate (OCR) of LQB303-treated extracellular amastigotes of T. cruzi, as well as reduction of “proton leak” (the depletion of proton motive force by the inhibition of F1Fo ATP synthase) and “ETS” (maximal oxygen consumption after uncoupling) oxygen consumption rates. Interestingly, the residual respiration (“ROX”) enhanced about three times in LQB303-treated amastigotes. The spare respiratory capacity ratio (SRC: cell ability to meet new energy demands) and the ATP-linked OCR were also impaired by LQB303 treatment, correlating the trypanocidal activity of LQB303 with the impairment of mitochondrial redox metabolism of amastigotes. Flow cytometric analysis demonstrated a significant reduction of the ΔΨm of treated amastigotes. LQB303 had no significant influence on the OCR of treated mammalian cells, evidencing its specificity against T. cruzi mitochondrial metabolism. Our results suggest a promising trypanocidal activity of LQB303, associated with parasite bioenergetic inefficiency, with no influence on the host energy metabolism, a fact that may point to an attractive alternative therapy for Chagas disease.https://www.frontiersin.org/articles/10.3389/fmicb.2021.617504/fullTrypanosoma cruzichemotherapybioenergeticshigh-resolution respirometrymitochondriontropical neglected disease |
| spellingShingle | Carolina Machado Macedo Francis Monique de Souza Saraiva Jéssica Isis Oliveira Paula Suelen de Brito Nascimento Suelen de Brito Nascimento Débora de Souza dos Santos Costa Paulo Roberto Ribeiro Costa Ayres Guimarães Dias Marcia Cristina Paes Marcia Cristina Paes Natália Pereira Nogueira Natália Pereira Nogueira The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi Frontiers in Microbiology Trypanosoma cruzi chemotherapy bioenergetics high-resolution respirometry mitochondrion tropical neglected disease |
| title | The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi |
| title_full | The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi |
| title_fullStr | The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi |
| title_full_unstemmed | The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi |
| title_short | The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi |
| title_sort | potent trypanocidal effect of lqb303 a novel redox active phenyl tert butyl nitrone derivate that causes mitochondrial collapse in trypanosoma cruzi |
| topic | Trypanosoma cruzi chemotherapy bioenergetics high-resolution respirometry mitochondrion tropical neglected disease |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2021.617504/full |
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