Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action
BACKGROUND Leishmania parasites cause leishmaniasis that range from self-limiting cutaneous lesions to more serious forms of the disease. The search for potential drug targets focusing on biochemical and metabolic pathways revealed the sterol biosynthesis inhibitors (SBIs) as a promising approach....
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Format: | Article |
Language: | English |
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Fundação Oswaldo Cruz (FIOCRUZ)
2022-04-01
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Series: | Memorias do Instituto Oswaldo Cruz |
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Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762022000101105&tlng=en |
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author | Débora Cristina de Oliveira Silva Nunes Mônica Soares Costa Luiz Borges Bispo-da-Silva Eloísa Amália Vieira Ferro Mariana Alves Pereira Zóia Luiz Ricardo Goulart Renata Santos Rodrigues Veridiana de Melo Rodrigues Kelly Aparecida Geraldo Yoneyama |
author_facet | Débora Cristina de Oliveira Silva Nunes Mônica Soares Costa Luiz Borges Bispo-da-Silva Eloísa Amália Vieira Ferro Mariana Alves Pereira Zóia Luiz Ricardo Goulart Renata Santos Rodrigues Veridiana de Melo Rodrigues Kelly Aparecida Geraldo Yoneyama |
author_sort | Débora Cristina de Oliveira Silva Nunes |
collection | DOAJ |
description | BACKGROUND Leishmania parasites cause leishmaniasis that range from self-limiting cutaneous lesions to more serious forms of the disease. The search for potential drug targets focusing on biochemical and metabolic pathways revealed the sterol biosynthesis inhibitors (SBIs) as a promising approach. In this class of inhibitors is found ketoconazole, a classical inhibitor of 14α-methysterol 14-demethylase. OBJECTIVE The present study aimed to better understand the biological response of Leishmania (Leishmania) amazonensis promastigotes at the cellular level after ketoconazole treatment. METHODS Herein, techniques, such as fluorimetry, flow cytometry, fluorescence microscopy, electron and scanning microscopy were used to investigate the cellular structures and to identify organelles affected by ketoconazole treatment. FINDINGS The study demonstrated, for the first time, the effect of ketoconazole on mitochondrion functioning and its probable relationship to cell cycle and death on L. (L.) amazonensis promastigotes (IFLA/BR/67/PH8 strain). MAIN CONCLUSIONS Ketoconazole-induced mitochondrial damages led to hyperpolarisation of this single organelle and autophagic vacuoles formation, as a parasite survival strategy. These damages did not reflect directly on the parasite cell cycle, but drove the parasites to death, making them susceptible to ketoconazole treatment in in vitro models. |
first_indexed | 2024-03-12T09:24:44Z |
format | Article |
id | doaj.art-e0d0dd2f0176485db6a161b67876c082 |
institution | Directory Open Access Journal |
issn | 1678-8060 |
language | English |
last_indexed | 2024-03-12T09:24:44Z |
publishDate | 2022-04-01 |
publisher | Fundação Oswaldo Cruz (FIOCRUZ) |
record_format | Article |
series | Memorias do Instituto Oswaldo Cruz |
spelling | doaj.art-e0d0dd2f0176485db6a161b67876c0822023-09-02T14:21:06ZengFundação Oswaldo Cruz (FIOCRUZ)Memorias do Instituto Oswaldo Cruz1678-80602022-04-0111710.1590/0074-02760210157Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of actionDébora Cristina de Oliveira Silva NunesMônica Soares CostaLuiz Borges Bispo-da-SilvaEloísa Amália Vieira FerroMariana Alves Pereira ZóiaLuiz Ricardo GoulartRenata Santos RodriguesVeridiana de Melo RodriguesKelly Aparecida Geraldo Yoneyamahttps://orcid.org/0000-0003-0329-5521 BACKGROUND Leishmania parasites cause leishmaniasis that range from self-limiting cutaneous lesions to more serious forms of the disease. The search for potential drug targets focusing on biochemical and metabolic pathways revealed the sterol biosynthesis inhibitors (SBIs) as a promising approach. In this class of inhibitors is found ketoconazole, a classical inhibitor of 14α-methysterol 14-demethylase. OBJECTIVE The present study aimed to better understand the biological response of Leishmania (Leishmania) amazonensis promastigotes at the cellular level after ketoconazole treatment. METHODS Herein, techniques, such as fluorimetry, flow cytometry, fluorescence microscopy, electron and scanning microscopy were used to investigate the cellular structures and to identify organelles affected by ketoconazole treatment. FINDINGS The study demonstrated, for the first time, the effect of ketoconazole on mitochondrion functioning and its probable relationship to cell cycle and death on L. (L.) amazonensis promastigotes (IFLA/BR/67/PH8 strain). MAIN CONCLUSIONS Ketoconazole-induced mitochondrial damages led to hyperpolarisation of this single organelle and autophagic vacuoles formation, as a parasite survival strategy. These damages did not reflect directly on the parasite cell cycle, but drove the parasites to death, making them susceptible to ketoconazole treatment in in vitro models.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762022000101105&tlng=encutaneous leishmaniasisergosterolmitochondrial damagesterol biosynthesis inhibitor |
spellingShingle | Débora Cristina de Oliveira Silva Nunes Mônica Soares Costa Luiz Borges Bispo-da-Silva Eloísa Amália Vieira Ferro Mariana Alves Pereira Zóia Luiz Ricardo Goulart Renata Santos Rodrigues Veridiana de Melo Rodrigues Kelly Aparecida Geraldo Yoneyama Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action Memorias do Instituto Oswaldo Cruz cutaneous leishmaniasis ergosterol mitochondrial damage sterol biosynthesis inhibitor |
title | Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action |
title_full | Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action |
title_fullStr | Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action |
title_full_unstemmed | Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action |
title_short | Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action |
title_sort | mitochondrial dysfunction on leishmania leishmania amazonensis induced by ketoconazole insights into drug mode of action |
topic | cutaneous leishmaniasis ergosterol mitochondrial damage sterol biosynthesis inhibitor |
url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762022000101105&tlng=en |
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