Venom alkaloids against Chagas disease parasite: search for effective therapies

Rafael C M Costa Silva,Isabela Ramos,Tatiana F R Costa,Fabio M Gomes,Ednildo De Alcântara Machado,Georgia C Atella,Guillermo D Alonso,Alejandra C Schoijet,Nathalia S Rodrigues,Kildare Miranda,Norton Heise,Daniel F Feijó,Carolina M Koeller,Eduardo G P Fox,Ana P Lima

doi:10.1038/s41598-020-67324-8

Abstract

Chagas disease is an important disease affecting millions of patients in the New World and is caused by a protozoan transmitted by haematophagous kissing bugs. It can be treated with drugs during the early acute phase; however, effective therapy against the chronic form of Chagas disease has yet to be discovered and developed. We herein tested the activity of solenopsin alkaloids extracted from two species of fire ants against the protozoan parasite Trypanosoma cruzi, the aetiologic agent of Chagas disease. Although IC50 determinations showed that solenopsins are more toxic to the parasite than benznidazole, the drug of choice for Chagas disease treatment, the ant alkaloids presented a lower selectivity index. As a result of exposure to the alkaloids, the parasites became swollen and rounded in shape, with hypertrophied contractile vacuoles and intense cytoplasmic vacuolization, possibly resulting in osmotic stress; no accumulation of multiple kinetoplasts and/or nuclei was detected. Overexpressing phosphatidylinositol 3-kinase—an enzyme essential for osmoregulation that is a known target of solenopsins in mammalian cells—did not prevent swelling and vacuolization, nor did it counteract the toxic effects of alkaloids on the parasites. Additional experimental results suggested that solenopsins induced a type of autophagic and programmed cell death in T. cruzi. Solenopsins also reduced the intracellular proliferation of T. cruzi amastigotes in infected macrophages in a concentration-dependent manner and demonstrated activity against Trypanosoma brucei rhodesiense bloodstream forms, which is another important aetiological kinetoplastid parasite. The results suggest the potential of solenopsins as novel natural drugs against neglected parasitic diseases caused by kinetoplastids.

Highlights

Chagas disease is an important disease affecting millions of patients in the New World and is caused by a protozoan transmitted by haematophagous kissing bugs
Total ion chromatograms (Fig. S1) illustrate the diversity of solenopsin analogues found in the venom of each fire ant species, and their chemical structures and distribution are presented in Fig. 1 and Table 1, respectively
Parasites treated with either solenopsin extracts within the range of 0.25–0.5 × IC50 values for up to 8 days later recovered culture growth capacity when the solenopsins were removed (Fig. S2C), indicating that the replication inhibition induced by solenopsins is reversible

Summary

Introduction

Chagas disease is an important disease affecting millions of patients in the New World and is caused by a protozoan transmitted by haematophagous kissing bugs It can be treated with drugs during the early acute phase; effective therapy against the chronic form of Chagas disease has yet to be discovered and developed. We tested the activity of solenopsin alkaloids extracted from two species of fire ants against the protozoan parasite Trypanosoma cruzi, the aetiologic agent of Chagas disease. Aka American trypanosomiasis, is a potentially life-threatening disorder caused by different strains of the protozoan Trypanosoma cruzi, currently affecting approximately 8 million individuals worldwide (and estimated 25 million people are at risk), leading to over 10,000 deaths per year[22]. Studies concerning the activity of alkaloids from animal venoms against protozoan parasites have never been performed

Methods

Results

Conclusion