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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Main Authors: 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
Format: Article
Language:English
Published: Fundação Oswaldo Cruz (FIOCRUZ) 2022-04-01
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.
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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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