Treatment of Trypanosoma cruzi with 2-bromopalmitate alters morphology, endocytosis, differentiation and infectivity

Batista, Cassiano Martin; Kessler, Rafael Luis; Eger, Iriane; Soares, Maurílio J.

doi:10.1186/s12860-018-0170-3

Cited by 9 publications

(8 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The phenotypic effect of crosstalk was further studied by measuring P. falciparum growth inhibition against individual and combinatorial treatments with ST092793 and 2-BMP which are generic inhibitors of phosphorylation and palmitoylation, respectively. Although 2-BMP is known to have non-specific effects ( DeJesus and Bizzozero, 2002 ; Zheng et al., 2015 ), it has been used extensively to target palmitoylation-based pathways in L. donovani , T. cruzi , and Toxoplasma ( Foe et al., 2015 ; Ayana et al., 2018 ; Batista et al., 2018b ; Batista et al., 2018a ) for reducing infectivity. Plausibly, one of our recent unpublished data has also shown that 2-BMP has no impact on overall morphology of host RBCs.…”

Section: Discussionmentioning

confidence: 99%

Complementary crosstalk between palmitoylation and phosphorylation events in MTIP regulates its role during Plasmodium falciparum invasion

Anam

Kumari²,

Mukherjee³

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Post-translational modifications (PTMs) including phosphorylation and palmitoylation have emerged as crucial biomolecular events that govern many cellular processes including functioning of motility- and invasion-associated proteins during Plasmodium falciparum invasion. However, no study has ever focused on understanding the possibility of a crosstalk between these two molecular events and its direct impact on preinvasion- and invasion-associated protein–protein interaction (PPI) network-based molecular machinery. Here, we used an integrated in silico analysis to enrich two different catalogues of proteins: (i) the first group defines the cumulative pool of phosphorylated and palmitoylated proteins, and (ii) the second group represents a common set of proteins predicted to have both phosphorylation and palmitoylation. Subsequent PPI analysis identified an important protein cluster comprising myosin A tail interacting protein (MTIP) as one of the hub proteins of the glideosome motor complex in P. falciparum, predicted to have dual modification with the possibility of a crosstalk between the same. Our findings suggested that blocking palmitoylation led to reduced phosphorylation and blocking phosphorylation led to abrogated palmitoylation of MTIP. As a result of the crosstalk between these biomolecular events, MTIP’s interaction with myosin A was found to be abrogated. Next, the crosstalk between phosphorylation and palmitoylation was confirmed at a global proteome level by click chemistry and the phenotypic effect of this crosstalk was observed via synergistic inhibition in P. falciparum invasion using checkerboard assay and isobologram method. Overall, our findings revealed, for the first time, an interdependence between two PTM types, their possible crosstalk, and its direct impact on MTIP-mediated invasion via glideosome assembly protein myosin A in P. falciparum. These insights can be exploited for futuristic drug discovery platforms targeting parasite molecular machinery for developing novel antimalarial therapeutics.

show abstract

Section: Discussionmentioning

confidence: 99%

Complementary crosstalk between palmitoylation and phosphorylation events in MTIP regulates its role during Plasmodium falciparum invasion

Anam

Kumari²,

Mukherjee³

et al. 2022

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…A similar titrated inhibitor-based approach as described above was followed to inhibit fatty acid oxidation in fresh and desiccated Aedes eggs, and 0.8 mM of 2-bromopalmitic acid (Sigma Aldrich, 238422) was added to fresh blood used for feeding 10 days old female mosquitoes. This concentration was specifically chosen based on our optimised range for DFMO treatment which served as a reference and from published data by [ 77 ]. Higher doses of the drug (>1.2 mM) led to the mortality of adult females.…”

Section: Methodsmentioning

confidence: 99%

Eggs of the mosquito Aedes aegypti survive desiccation by rewiring their polyamine and lipid metabolism

Prasad,

Sreedharan,

Bakthavachalu

et al. 2023

PLoS Biol

View full text Add to dashboard Cite

Upon water loss, some organisms pause their life cycles and escape death. While widespread in microbes, this is less common in animals. Aedes mosquitoes are vectors for viral diseases. Aedes eggs can survive dry environments, but molecular and cellular principles enabling egg survival through desiccation remain unknown. In this report, we find that Aedes aegypti eggs, in contrast to Anopheles stephensi, survive desiccation by acquiring desiccation tolerance at a late developmental stage. We uncover unique proteome and metabolic state changes in Aedes embryos during desiccation that reflect reduced central carbon metabolism, rewiring towards polyamine production, and enhanced lipid utilisation for energy and polyamine synthesis. Using inhibitors targeting these processes in blood-fed mosquitoes that lay eggs, we infer a two-step process of desiccation tolerance in Aedes eggs. The metabolic rewiring towards lipid breakdown and dependent polyamine accumulation confers resistance to desiccation. Furthermore, rapid lipid breakdown is required to fuel energetic requirements upon water reentry to enable larval hatching and survival upon rehydration. This study is fundamental to understanding Aedes embryo survival and in controlling the spread of these mosquitoes.

show abstract

“…Vero cells (CCL-81) isolated from the kidney of the African green monkey Cercopithecus aethiops [ 17 ] were purchased from ATCC® (Washington DC, USA). The cells were inoculated in 200 μL of Dulbecco’s modified Eagle (DMEM) medium in 96-well plates at a concentration of 2 × 10 4 cells/well and incubated at 37°C for 24 h for adherence of the cells [ 18 ]. Six different concentrations of the compounds (12 to 900 μM for butanolides, and 200 to 1,600 μM for benznidazole) were added to the wells.…”

Section: Methodsmentioning

confidence: 99%

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

et al. 2021

View full text Add to dashboard Cite

Butanolides have shown a variety of biological effects including anti-inflammatory, antibacterial, and antiprotozoal effects against certain strains of Trypanosoma cruzi. Considering the lack of an effective drug to treat T. cruzi infections and the prominent results obtained in literature with this class of lactones, we investigated the anti-T. cruzi activity of five butanolides isolated from two species of Lauraceae, Aiouea trinervis and Mezilaurus crassiramea. Initially, the activity of these compounds was evaluated on epimastigote forms of the parasite, after a treatment period of 4 h, followed by testing on amastigotes, trypomastigotes, and mammalian cells. Next, the synergistic effect of active butanolides against amastigotes was evaluated. Further, metacyclogenesis inhibition and infectivity assays were performed for the most active compound, followed by ultrastructural analysis of the treated amastigotes and trypomastigotes. Among the five butanolides studied, majoranolide and isoobtusilactone A were active against all forms of the parasite, with good selectivity indexes in Vero cells. Both butanolides were more active than the control drug against trypomastigote and epimastigote forms and also had a synergic effect on amastigotes. The most active compound, isoobtusilactone A, which showed activity against all tested strains inhibited metacyclogenesis and infection of new host cells. In addition, ultrastructural analysis revealed that this butanolide caused extensive damage to the mitochondria of both amastigotes and trypomastigotes, resulting in severe morphological changes in the infective forms of the parasite. Altogether, our results highlight the potential of butanolides against the etiologic agent of Chagas disease and the relevance of isoobtusilactone A as a strong anti-T. cruzi drug, affecting different events of the life cycle and all evolutionary forms of parasite after a short period of exposure.

show abstract

Treatment of Trypanosoma cruzi with 2-bromopalmitate alters morphology, endocytosis, differentiation and infectivity

Cited by 9 publications

References 56 publications

Complementary crosstalk between palmitoylation and phosphorylation events in MTIP regulates its role during Plasmodium falciparum invasion

Complementary crosstalk between palmitoylation and phosphorylation events in MTIP regulates its role during Plasmodium falciparum invasion

Eggs of the mosquito Aedes aegypti survive desiccation by rewiring their polyamine and lipid metabolism

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

Contact Info

Product

Resources

About