Protean permeases: Diverse roles for membrane transport proteins in kinetoplastid protozoa

Landfear, Scott M.

doi:10.1016/j.molbiopara.2018.12.006

Cited by 5 publications

(3 citation statements)

References 72 publications

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“…Currently, chemotherapy is the only available option against trypanosomes as efforts to develop a vaccine have been thwarted by the international community, however, the development of trypanocidal resistance has become a realistic threat especially for persons living in endemic regions (103,145,157,158). Trypanosoma transport proteins [on the surface of the parasite (see Table 4)] are responsible for pathogen survival; and trypanocidal resistance has been associated with changes in the pathogen transportome leading to dysfunction and a loss in therapeutical potential once drugs can no longer be absorbed by the parasite (152)(153)(154)159). This justifies the need to promote further research for the discovery of novel chemotherapeutical options for the control of trypanosomiasis.…”

Section: Trypanocidal Resistancementioning

confidence: 99%

An Update on African Trypanocide Pharmaceutics and Resistance

et al. 2022

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African trypanosomiasis is associated with Trypanosoma evansi, T. vivax, T. congolense, and T. brucei pathogens in African animal trypanosomiasis (AAT) while T. b gambiense and T. b rhodesiense are responsible for chronic and acute human African trypanosomiasis (HAT), respectively. Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against T. vivax and T. congolense infections. Resistance to suramin is associated with pathogen altered transport proteins. Melarsoprol binds irreversibly with pyruvate kinase protein sulfhydryl groups and neutralizes enzymes which interrupts the trypanosome ATP generation. Melarsoprol resistance is associated with the adenine-adenosine transporter, P2, due to point mutations within this transporter. Eflornithine is used in combination with nifurtimox. Resistance to eflornithine is caused by the deletion or mutation of TbAAT6 gene which encodes the transmembrane amino acid transporter that delivers eflornithine into the cell, thus loss of transporter protein results in eflornithine resistance. Nifurtimox alone is regarded as a poor trypanocide, however, it is effective in melarsoprol-resistant gHAT patients. Resistance is associated with loss of a single copy of the genes encoding for nitroreductase enzymes. Fexinidazole is recommended for first-stage and non-severe second-stage illnesses in gHAT and resistance is associated with trypanosome bacterial nitroreductases which reduce fexinidazole. In AAT, quinapyramine sulfate interferes with DNA synthesis and suppression of cytoplasmic ribosomal activity in the mitochondria. Quinapyramine sulfate resistance is due to variations in the potential of the parasite's mitochondrial membrane. Pentamidines create cross-links between two adenines at 4–5 pairs apart in adenine-thymine-rich portions of Trypanosoma DNA. It also suppresses type II topoisomerase in the mitochondria of Trypanosoma parasites. Pentamidine resistance is due to loss of mitochondria transport proteins P2 and HAPT1. Diamidines are most effective against Trypanosome brucei group and act via the P2/TbAT1 transporters. Diminazene aceturate resistance is due to mutations that alter the activity of P2, TeDR40 (T. b. evansi). Isometamidium chloride is primarily employed in the early stages of trypanosomiasis and resistance is associated with diminazene resistance. Phenanthridine (homidium bromide, also known as ethidium bromide) acts by a breakdown of the kinetoplast network and homidium resistance is comparable to isometamidium. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT.

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Section: Trypanocidal Resistancementioning

confidence: 99%

An Update on African Trypanocide Pharmaceutics and Resistance

et al. 2022

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“…These DEGs plus the downregulated gene putatively coding for cytosolic malate dehydrogenase (TcCLB.506937.10) and the upregulation of several genes coding for amino acid permeases and transporters (5 putative permeases and one transporter (TcCLB.508923.10, TcCLB.511325.40, TcCLB.507811.100, TcCLB.511325.50, TcCLB.507101.10, TcCLB.511325.25) describe a global profile coinciding with the starvation-induced metabolic switch from glucose to amino acid consumption previously reported ( Barisón et al., 2017 ). A wide range of biological functions has been proposed for cell or intracellular membrane transport proteins of kinetoplastids, establishing physiological properties such as membrane potential and responses to osmolarity, and in sensing and responding to changes in the environment ( Landfear, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic analysis of the adaptation to prolonged starvation of the insect-dwelling Trypanosoma cruzi epimastigotes

Smircich

Pérez-Díaz

Hernández

et al. 2023

Front. Cell. Infect. Microbiol.

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Trypanosoma cruzi is a digenetic unicellular parasite that alternates between a blood-sucking insect and a mammalian, host causing Chagas disease or American trypanosomiasis. In the insect gut, the parasite differentiates from the non-replicative trypomastigote forms that arrive upon blood ingestion to the non-infective replicative epimastigote forms. Epimastigotes develop into infective non-replicative metacyclic trypomastigotes in the rectum and are delivered via the feces. In addition to these parasite stages, transitional forms have been reported. The insect-feeding behavior, characterized by few meals of large blood amounts followed by long periods of starvation, impacts the parasite population density and differentiation, increasing the transitional forms while diminishing both epimastigotes and metacyclic trypomastigotes. To understand the molecular changes caused by nutritional restrictions in the insect host, mid-exponentially growing axenic epimastigotes were cultured for more than 30 days without nutrient supplementation (prolonged starvation). We found that the parasite population in the stationary phase maintains a long period characterized by a total RNA content three times smaller than that of exponentially growing epimastigotes and a distinctive transcriptomic profile. Among the transcriptomic changes induced by nutrient restriction, we found differentially expressed genes related to managing protein quality or content, the reported switch from glucose to amino acid consumption, redox challenge, and surface proteins. The contractile vacuole and reservosomes appeared as cellular components enriched when ontology term overrepresentation analysis was carried out, highlighting the roles of these organelles in starving conditions possibly related to their functions in regulating cell volume and osmoregulation as well as metabolic homeostasis. Consistent with the quiescent status derived from nutrient restriction, genes related to DNA metabolism are regulated during the stationary phase. In addition, we observed differentially expressed genes related to the unique parasite mitochondria. Finally, our study identifies gene expression changes that characterize transitional parasite forms enriched by nutrient restriction. The analysis of the here-disclosed regulated genes and metabolic pathways aims to contribute to the understanding of the molecular changes that this unicellular parasite undergoes in the insect vector.

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“…Here, different drug combination regimens were tested in vitro on the epimastigote culture, finding that a simultaneous combination of IVM-BZN and IVM-NFX showed mainly additive effects; however, some combinations showed significant antagonistic or synergic effects. These effects could be explained by different described mechanisms of IVM action, including an antagonism by increasing detoxification processes induced by this drug that avoid the effects of NFX or BZN ( Lespine et al., 2007 ; Ménez et al., 2012 ; Nodari et al., 2020 ) or a synergism by inhibiting the activity of P-gp, a member of the superfamily of transporters ABC (ATP-binding cassette), that enhances the cytotoxicity of other drugs ( Furusawa et al., 2000 ; Landfear, 2019 ). As mentioned by other authors, the in vitro assays about the interaction between two drugs are usually the first-step studies, although the observed results do not necessarily reflect the in vivo effects; pharmacokinetic and host factors (as the immune response) may lead to different outcomes due to the modification of the effective exposure of the parasites to the drugs ( Vincent et al., 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids

Fraccaroli

Ruiz

Perdomo

et al. 2022

Front. Cell. Infect. Microbiol.

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Chagas disease is an endemic American parasitosis, caused by Trypanosoma cruzi. The current therapies, benznidazole (BZN) and nifurtimox (NFX), show limited efficacy and multiple side effects. Thus, there is a need to develop new trypanocidal strategies. Ivermectin (IVM) is a broad-spectrum antiparasitic drug with low human and veterinary toxicity with effects against T. brucei and Leishmania spp. Considering this and its relatively low cost, we evaluate IVM as a potential repurposed trypanocidal drug on T. cruzi and other trypanosomatids. We found that IVM affected, in a dose-dependent manner, the proliferation of T. cruzi epimastigotes as well as the amastigotes and trypomastigotes survival. The Selectivity Index for the amastigote stage with respect to Vero cells was 12. The IVM effect was also observed in Phytomonas jma 066 and Leishmania mexicana proliferation but not in Crithidia fasciculata. On the epimastigote stage, the IVM effect was trypanostatic at 50 μM but trypanocidal at 100 μM. The assays of the drug combinations of IVM with BNZ or NFX showed mainly additive effects among combinations. In silico studies showed that classical structures belonging to glutamate-gated Cl channels, the most common IVM target, are absent in kinetoplastids. However, we found in the studied trypanosomatid genomes one copy for putative IMPα and IMPβ, potential targets for IVM. The putative IMPα genes (with 76% similarity) showed conserved Armadillo domains but lacked the canonical IMPβ binding sequence. These results allowed us to propose a novel molecular target in T. cruzi and suggest IVM as a good candidate for drug repurposing in the Chagas disease context.

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Protean permeases: Diverse roles for membrane transport proteins in kinetoplastid protozoa

Cited by 5 publications

References 72 publications

An Update on African Trypanocide Pharmaceutics and Resistance

An Update on African Trypanocide Pharmaceutics and Resistance

Transcriptomic analysis of the adaptation to prolonged starvation of the insect-dwelling Trypanosoma cruzi epimastigotes

Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids

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