Evaluation of Beauvericin’s activity and mode of action against all life stages of L. tropica for cutaneous Leishmaniasis therapy

TL;DR

This study explores Beauvericin, a natural compound, as a potential new treatment for leishmaniasis that works against all stages of the parasite and is less likely to cause drug resistance.

Contribution

The study demonstrates Beauvericin's broad efficacy and unique mechanism of action against Leishmania tropica, with a lower resistance development rate compared to existing drugs.

Findings

Beauvericin showed potent activity against both promastigote and amastigote stages of L. tropica with low IC50 values.

Beauvericin acts as a calcium ionophore, causing calcium dysregulation and triggering multiple cellular stress responses.

In a Galleria mellonella model, Beauvericin reduced parasite burden and improved survival rates with slower resistance development.

Abstract

Leishmaniasis, particularly its cutaneous form caused by Leishmania tropica, remains a significant global health concern due to the limitations of current treatments, including drug resistance, toxicity, and inconsistent efficacy. This study investigates the potential of Beauvericin (BEA), a fungal secondary metabolite, as an alternative antileishmanial agent.

This study investigates the potential of Beauvericin (BEA), a fungal secondary metabolite, as an alternative antileishmanial agent.

We assessed the efficacy of BEA against different developmental stages of L. tropica using in vitro assays and an in vivo Galleria mellonella infection model. The ability of L. tropica to develop resistance to BEA and its effects on the parasite’s gene expression profile were also examined.

BEA exhibited potent antileishmanial activity with equipotency across both promastigote and amastigote stages of L. tropica, with IC50 values of 0.25 µM and 0.27 µM, respectively, significantly lower than those of miltefosine. Mechanistically, BEA acts as a calcium ionophore, inducing a marked increase in intracellular calcium levels, which serves as the primary cytotoxic event. Transcriptomic profiling further revealed that BEA-induced calcium dysregulation triggers secondary cellular responses involving calcium homeostasis, lipid metabolism, and stress response, contributing to its multifaceted mechanism of action. The G. mellonella model demonstrated that BEA significantly reduced parasite burden, improved survival rates. Notably, BEA showed a slower rate of resistance development compared to ML, indicating its potential as a more sustainable treatment option.

BEA is a promising candidate for antileishmanial therapy, demonstrating superior efficacy, a broad mechanism of action, and a favorable resistance profile compared to ML. Further investigations in mammalian models are warranted to validate BEA’s potential as a novel, cost-effective treatment for leishmaniasis.

Figures