<i>In Vitro</i> and <i>In Vivo</i> Leishmanicidal Activity of Beauvericin

Leishmaniasis is a worldwide disease caused by more than 20 species of <i>Leishmania</i> parasites. <i>Leishmania amazonensis</i> and <i>L. braziliensis</i> are among the main causative agents of cutaneous leishmaniasis, presenting a broad spectrum of clinical forms. As these pathologies lead to unsatisfactory treatment outcomes, the discovery of alternative chemotherapeutic options is urgently required. In this investigation, a leishmanicidal bioassay-guided fractionation of the growth media extract produced by <i>Aspergillus terreus</i> P63 led to the isolation of the cyclic depsipeptide beauvericin (<b>1</b>). The viability of <i>L. amazonensis</i>, <i>L. braziliensis</i> and mammalian cells (macrophages and L929 fibroblasts) was assessed in <b>1</b> incubated cultures. <i>Leishmania</i> promastigotes were sensitive to <b>1</b>, with EC₅₀ values ranging from 0.7 to 1.3 μM. Microscopy analysis indicated that <i>Leishmania</i> spp. parasites showed morphological abnormalities in a dose-dependent manner in the presence of <b>1</b>. <i>L. amazonensis</i> intracellular amastigotes were more sensitive to <b>1</b> than promastigotes (EC₅₀ = 0.8 ± 0.1 μM), with a good selectivity index (22-30). <b>1</b> reduced the infectivity index at very low concentrations, maintaining the integrity of the primary murine host cell for up to the highest concentration tested for <b>1</b>. <i>In vivo</i> assays of <b>1</b> conducted using BALB/c mice infected with stationary-phase promastigotes of <i>L. amazonensis</i> in the tail base presented a significant reduction in the lesion parasite load. A second round of <i>in vivo</i> assays was performed to assess the efficacy of the topical use of <b>1</b>. The results demonstrated a significant decrease in the total ulcerated area of mice treated with <b>1</b> when compared with untreated animals. Our results present promising <i>in vitro</i> and <i>in vivo</i> leishmanicidal effects of beauvericin, emphasizing that systemic inoculation of <b>1</b> led to a decrease in the parasite load at the lesion site, whereas topical administration of <b>1</b> delayed the progression of leishmaniasis ulcers, a cure criterion established for cutaneous leishmaniasis management.