Abstract
Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents.
Highlights
The leishmaniases, which are among the most prevalent neglected tropical diseases, are caused by protozoan parasites of the Leishmania genus
Selectivity indexes were calculated using the IC50 values obtained after 72 h of treatment, and ITZ was more selective than POSA in vitro (Table 1)
Previous studies demonstrated that POSA has potent antiparasitic activity in a murine model of cutaneous leishmaniasis caused by Leishmania amazonensis, it was less active against visceral leishmaniasis caused by Leishmania donovani [18]
Summary
The leishmaniases, which are among the most prevalent neglected tropical diseases, are caused by protozoan parasites of the Leishmania genus. More than 90% of cases of visceral leishmaniasis and cutaneous leishmaniases occur in India, Sudan, Bangladesh, Nepal, Brazil, Afghanistan, Saudi Arabia, Algeria, Iran, Iraq and Syria [1]. When the immune system fails to mount an appropriate response against the parasite, L. amazonensis can cause clinical manifestations of diffuse cutaneous leishmaniasis [5]. It is a serious public health problem in Brazil, because the lesions cover a large part of the body, sometimes producing mutilated lesions, and is devastating for the patients, because it is incurable using currently available treatments
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