Venom alkaloids against Chagas disease parasite: search for effective therapies

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 IC 50 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. Alkaloids are organic compounds containing a nitrogen atom usually associated with the cyclic chain within its structure 1. They are a large, diverse group of chemicals, in which some compounds are known as poisons (e.g., strychnine), stimulants (e.g., caffeine), and analgesics (e.g., morphine) 2. Alkaloids are mostly found in plants but have also been identified from a number of animals, such as frogs and ants 1. Recently, several studies have evaluated the potential of antimicrobial alkaloids as prospective new drugs against diseases caused by bacteria 3

Biological Activities and Ecological Significance of Fire Ant Venom Alkaloids

“…Chagas disease, caused by the protozoan parasite Trypanosoma cruzi and transmitted by haematophagous triatomine bugs, is an important disease affecting millions of individuals in the New World. The alkaloids extracted from fire ants Solenopsis saevissima and S. invicta are toxic to T. cruzi amastigotes and epimastigotes [ 86 ]. They induce morphological alterations in T. cruzi epimastigotes, prompting hypertrophied contractile vacuoles and intense cytoplasmic vacuolization.…”

“…IC 50 values for the two venoms are similar against the epimastigote and amastigote forms of T. cruzi . The growth inhibitory effects of fire ant venom alkaloids on T. cruzi epimastigotes are reversible [ 86 ].…”

Chemistry and Functions of Imported Fire Ant Venom

“…To combat infectious diseases, ants commonly use gland secretions as external disinfectants [ 96 , 97 , 98 , 99 ]. The antimicrobial properties of fire ant venom alkaloids and their analogs have been extensively studied [ 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ], including their activities against bacteria, fungi, microsporidia, and entomopathogenic pathogens. Recent research has provided evidence suggesting that fire ant venom may also function as an internal antibiotic [ 28 ].…”

Different Drugs, Same End: Ultrastructural Hallmarks of Autophagy in Pathogenic Protozoa

“…The increased number of autophagosomes, a determinant of macroautophagy occurrence, is another very recurrent phenotype detected in treated protozoa ( Braga et al, 2005 ; Granthon et al, 2006 ; Uzcátegui et al, 2007 ; Dos Santos et al, 2010 ; Schurigt et al, 2010 ; Besteiro et al, 2011 ; Sengupta et al, 2011 ; Fernandes et al, 2012 ; Ghosh et al, 2012 ; Veiga-Santos et al, 2013 ; Souto et al, 2016 ; Nguyen et al, 2017b ; Scariot et al, 2017 ; Lim et al, 2018 ; Martínez-García et al, 2018 ; Hernandéz-García et al, 2019 ; Huang et al, 2019 ; de Paula et al, 2020 ; Silva et al, 2020 ; Nishi et al, 2021 ; Zhang et al, 2021 ).…”