Mitochondrial Dysfunction on Leishmania (Leishmania) Amazonensis Induced by Ketoconazole: Insights into Drug Mode of Action

Overview

Journal Mem Inst Oswaldo Cruz

Specialties Parasitology
Tropical Medicine

Date 2022 May 4

PMID 35508030

Authors

Debora Cristina de Oliveira Silva Nunes

Monica Soares Costa

Luiz Borges Bispo-da-Silva

Eloisa Amalia Vieira Ferro

Mariana Alves Pereira Zoia

Luiz Ricardo Goulart

Renata Santos Rodrigues

Veridiana de Melo Rodrigues

Kelly Aparecida Geraldo Yoneyama

Affiliations

Soon will be listed here.

Abstract

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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