# Exploring the in vitro and in vivo antileishmanial potential of Marizomib against Leishmania amazonensis and Leishmania infantum

## TL;DR

Marizomib shows promise as a treatment for leishmaniasis by effectively targeting the parasite in both lab and animal models without causing major toxicity.

## Contribution

Marizomib's selective antileishmanial activity against intracellular amastigotes and its efficacy in both cutaneous and visceral leishmaniasis models are newly demonstrated.

## Key findings

- Marizomib is effective against intracellular amastigotes of L. amazonensis and L. infantum but not promastigote forms.
- Marizomib reduces lesion size and parasite load in murine models of cutaneous and visceral leishmaniasis.
- Marizomib induces ultrastructural changes in amastigotes and does not cause acute renal or hepatic toxicity in infected animals.

## Abstract

Current treatment available for leishmaniasis is fraught with numerous problems, so the search for new treatment alternatives for leishmaniasis is urgent and necessary. The proteasome has been selected as a promising target. Marizomib is a proteasome inhibitor and has shown antitumor effects, with ongoing clinical tests. In this work, we aimed to evaluate the in vitro and in vivo effects of Marizomib on Leishmania amazonensis and Leishmania infantum. Interestingly, Marizomib was not effective against promastigote forms of L. amazonensis and L. infantum in vitro but showed a significant effect against intracellular amastigotes of L. amazonensis and L. infantum, showing selectivity for the parasite when compared to the host cell. Furthermore, through transmission electron microscopy, it was possible to show that Marizomib induces extensive ultrastructural changes in amastigotes of L. amazonensis and L. infantum, such as the appearance of many vacuoles in the parasite cytoplasm and mitochondrial swelling. Marizomib was also shown to be effective in a murine model of cutaneous leishmaniasis, with a reduction in the size of lesions and parasite load in the footpads and draining lymph nodes of animals infected with L. amazonensis. It is also effective in a model of visceral leishmaniasis, with a reduction in parasite load in the spleen and liver of animals infected with L. infantum. Importantly, Marizomib, in the treatment regimens used, did not cause renal and hepatic acute toxicity to infected animals. These results highlight the antileishmanial potential of Marizomib, encouraging us to conduct preclinical tests in other animal models, as well as clinical trials.