Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition

Steketee, Pieter C.; Dickie, Emily A.; Iremonger, James; Crouch, Kathryn; Paxton, Edith; Jayaraman, Siddharth; Alfituri, Omar A.; Awuah‐Mensah, Georgina; Ritchie, Ryan; Schnaufer, Achim; Rowan, T.G.; Koning, Harry P. de; Gadelha, Catarina; Wickstead, Bill; Barrett, Michael P.; Morrison, Liam J.

doi:10.1371/journal.ppat.1009734

Cited by 14 publications

(18 citation statements)

References 150 publications

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“…Therefore, glycolysis is important in both T. congolense and T. brucei for energy metabolism ( 43 ). Furthermore, the electron transport chain (ETC) is not required in T. congolense followed by substantial resistance to fatty acid synthesis inhibitors ( 44 , 45 ). These findings raise major challenges for chemotherapy development against drug resistance and host-pathogen interactions.…”

Section: The Trypanosoma Pathogenmentioning

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: The Trypanosoma Pathogenmentioning

confidence: 99%

An Update on African Trypanocide Pharmaceutics and Resistance

et al. 2022

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“…Though promising in culture and showing no apparent cytotoxicity towards the host, the O-11 myristate analog was ineffective in a mouse model of infection, apparently due to poor pharmacodynamics ( Werbovetz et al., 1996 ). Likewise, targeting one or both of the fatty acid uptake and de novo fatty acid synthesis machineries also could constitute a potential novel therapeutic target against T. brucei and other African trypanosomes ( Stephens et al., 2007 ; Steketee et al., 2021 ). Finally, the parasitic fatty acid uptake machinery could also be potentially exploited for new lipid-based drug delivery systems in the treatment of HAT and AAT ( Shrestha et al., 2014 ; Fattahi et al., 2020 ).…”

Section: Final Thoughtsmentioning

confidence: 99%

Fatty acid uptake in Trypanosoma brucei: Host resources and possible mechanisms

Poudyal

Paul

2022

Front. Cell. Infect. Microbiol.

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Trypanosoma brucei spp. causes African Sleeping Sickness in humans and nagana, a wasting disease, in cattle. As T. brucei goes through its life cycle in its mammalian and insect vector hosts, it is exposed to distinct environments that differ in their nutrient resources. One such nutrient resource is fatty acids, which T. brucei uses to build complex lipids or as a potential carbon source for oxidative metabolism. Of note, fatty acids are the membrane anchoring moiety of the glycosylphosphatidylinositol (GPI)-anchors of the major surface proteins, Variant Surface Glycoprotein (VSG) and the Procyclins, which are implicated in parasite survival in the host. While T. brucei can synthesize fatty acids de novo, it also readily acquires fatty acids from its surroundings. The relative contribution of parasite-derived vs. host-derived fatty acids to T. brucei growth and survival is not known, nor have the molecular mechanisms of fatty acid uptake been defined. To facilitate experimental inquiry into these important aspects of T. brucei biology, we addressed two questions in this review: (1) What is known about the availability of fatty acids in different host tissues where T. brucei can live? (2) What is known about the molecular mechanisms mediating fatty acid uptake in T. brucei? Finally, based on existing biochemical and genomic data, we suggest a model for T. brucei fatty acid uptake that proposes two major routes of fatty acid uptake: diffusion across membranes followed by intracellular trapping, and endocytosis of host lipoproteins.

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“…While decades of research on T. brucei have made this parasite a model organism for trypanosomatids, knowledge of the biology of T. congolense , the causative agent of African Animal Trypanosomiasis, is inadequate because of the limited ability to make genetic modifications. This has now been overcome, allowing important questions about the biology of the parasite to be addressed, including the fact that the mitochondrial metabolism of the bloodstream form of T. congolense appears to be more complex and developed than that of T. brucei (Awuah‐Mensah et al, 2021; Steketee et al, 2021). Furthermore, T. congolense is capable of undergoing the insect form differentiation process in culture without requiring any genetic manipulation, unlike T. brucei (Coustou et al, 2010; Gibson et al, 2017; Kolev et al, 2012).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Mitochondrial adaptations throughout the Trypanosoma brucei life cycle

Zı́ková

2022

J Eukaryotic Microbiology

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The unicellular parasite Trypanosoma brucei has a digenetic life cycle that alternates between a mammalian host and an insect vector. During programmed development, this extracellular parasite encounters strikingly different environments that determine its energy metabolism. Functioning as a bioenergetic, biosynthetic, and signaling center, the single mitochondrion of T. brucei is drastically remodeled to support the dynamic cellular demands of the parasite. This manuscript will provide an up‐to‐date overview of how the distinct T. brucei developmental stages differ in their mitochondrial metabolic and bioenergetic pathways, with a focus on the electron transport chain, proline oxidation, TCA cycle, acetate production, and ATP generation. Although mitochondrial metabolic rewiring has always been simply viewed as a consequence of the differentiation process, the possibility that certain mitochondrial activities reinforce parasite differentiation will be explored.

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Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition

Cited by 14 publications

References 150 publications

An Update on African Trypanocide Pharmaceutics and Resistance

An Update on African Trypanocide Pharmaceutics and Resistance

Fatty acid uptake in Trypanosoma brucei: Host resources and possible mechanisms

Mitochondrial adaptations throughout the Trypanosoma brucei life cycle

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