<i>In\nVitro</i> and <i>In Vivo</i> Leishmanicidal Activity\nof Beauvericin

Leishmaniasis is a worldwide disease caused by more than\n20 species\nof <i>Leishmania</i> parasites. <i>Leishmania amazonensis</i> and <i>L. braziliensis</i> are among the main causative\nagents of cutaneous leishmaniasis, presenting a broad spectrum of\nclinical forms. As these pathologies lead to unsatisfactory treatment\noutcomes, the discovery of alternative chemotherapeutic options is\nurgently required. In this investigation, a leishmanicidal bioassay-guided\nfractionation of the growth media extract produced by <i>Aspergillus\nterreus</i> P63 led to the isolation of the cyclic depsipeptide\nbeauvericin (<b>1</b>). The viability of <i>L. amazonensis</i>, <i>L. braziliensis</i> and mammalian cells (macrophages\nand L929 fibroblasts) was assessed in <b>1</b> incubated cultures. <i>Leishmania</i> promastigotes were sensitive to <b>1</b>, with EC<sub>50</sub> values ranging from 0.7 to 1.3 μM. Microscopy\nanalysis indicated that <i>Leishmania</i> spp. parasites\nshowed morphological abnormalities in a dose-dependent manner in the\npresence of <b>1</b>. <i>L. amazonensis</i> intracellular\namastigotes were more sensitive to <b>1</b> than promastigotes\n(EC<sub>50</sub> = 0.8 ± 0.1 μM), with a good selectivity\nindex (22–30). <b>1</b> reduced the infectivity index\nat very low concentrations, maintaining the integrity of the primary\nmurine host cell for up to the highest concentration tested for <b>1</b>. <i>In vivo</i> assays of <b>1</b> conducted\nusing BALB/c mice infected with stationary-phase promastigotes of <i>L. amazonensis</i> in the tail base presented a significant\nreduction in the lesion parasite load. A second round of <i>in\nvivo</i> assays was performed to assess the efficacy of the topical\nuse of <b>1</b>. The results demonstrated a significant decrease\nin the total ulcerated area of mice treated with <b>1</b> when\ncompared with untreated animals. Our results present promising <i>in vitro</i> and <i>in vivo</i> leishmanicidal effects\nof beauvericin, emphasizing that systemic inoculation of <b>1</b> led to a decrease in the parasite load at the lesion site, whereas\ntopical administration of <b>1</b> delayed the progression of\nleishmaniasis ulcers, a cure criterion established for cutaneous leishmaniasis\nmanagement.