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Adriana Botero, Irit Kapeller, Crystal Cooper, Peta L Clode, Joseph Shlomai, R C Andrew Thompson
Kinetoplast DNA (kDNA) is the mitochondrial genome of trypanosomatids. It consists of a few dozen maxicircles and several thousand minicircles, all catenated topologically to form a two-dimensional DNA network. Minicircles are heterogeneous in size and sequence among species. They present one or several conserved regions that contain three highly conserved sequence blocks (CSBs). CSB-1 (10 bp sequence) and CSB-2 (8 bp sequence) present lower interspecies homology, while CSB-3 (12 bp sequence) or the Universal Minicircle Sequence (UMS) is conserved within most trypanosomatids...
May 17, 2018: International Journal for Parasitology
Rosa Mª Reguer, Ehab Kotb Elmahallaw, Carlos Garcia-Estrada, Ruben Carbajo-Andres, Rafael Balana-Fouce
DNA topoisomerases (Top) are a group of isomerase enzymes responsible for controlling the topological problems caused by DNA double helix in the cell during the processes of replication, transcription and recombination. Interestingly, these enzymes have been known since long to be key molecular machines in several cellular processes through overwinding or underwinding of DNA in all-living organisms. Leishmania, a trypanosomatid parasite responsible for causing fatal diseases mostly in impoverished populations of low-income countries, have a set of six classes of Top enzymes...
May 17, 2018: Current Medicinal Chemistry
Lori Peacock, Christopher Kay, Mick Bailey, Wendy Gibson
Trypanosomatids such as Leishmania and Trypanosoma are digenetic, single-celled, parasitic flagellates that undergo complex life cycles involving morphological and metabolic changes to fit them for survival in different environments within their mammalian and insect hosts. According to current consensus, asymmetric division enables trypanosomatids to achieve the major morphological rearrangements associated with transition between developmental stages. Contrary to this view, here we show that the African trypanosome Trypanosoma congolense, an important livestock pathogen, undergoes extensive cell remodelling, involving shortening of the cell body and flagellum, during its transition from free-swimming proventricular forms to attached epimastigotes in vitro...
May 2018: PLoS Pathogens
José Rubén Ramírez-Iglesias, María Carolina Pérez-Gordones, Jesús Rafael Del Castillo, Alfredo Mijares, Gustavo Benaim, Marta Mendoza
The plasma membrane Ca2+ -ATPase (PMCA) from trypanosomatids lacks a classical calmodulin (CaM) binding domain, although CaM stimulated activities have been detected by biochemical assays. Recently we proposed that the Trypanosoma equiperdum CaM-sensitive PMCA (TePMCA) contains a potential 1-18 CaM-binding motif at the C-terminal region of the pump. In the present study, we evaluated the potential CaM-binding motifs using CaM from Trypanosoma cruzi and either the recombinant full length TePMCA C-terminal sequence (P14) or synthetic peptides comprising different regions of the C-terminal domain...
May 9, 2018: Molecular and Biochemical Parasitology
Ana Alonso, Vicente Larraga, Pedro J Alcolea
The first genome project of any living organism excluding viruses, the gammaproteobacteria Haemophilus influenzae, was completed in 1995. Until the last decade, genome sequencing was very tedious because genome survey sequences (GSS) and/or expressed sequence tags (ESTs) belonging to plasmid, cosmid and artificial chromosome genome libraries had to be sequenced and assembled in silico. Nowadays, no genome is completely assembled actually, because gaps and unassembled contigs are always remaining. However, most represent the whole genome of the organism of origin from a practical point of view...
May 7, 2018: Acta Tropica
Abdul Aziz A Bin Dukhyil
BACKGROUND: 1.2-2.0 million cases of leishmaniasis occur annually throughout the world. The available drugs like Amphotericin B, antimonials and miltefosine are unable to fulfill the need due less effectiveness, high toxicity, resistance, high cost and complex route of administration. Leishmania survives inside the macrophages through different evasion mechanisms; one of that is activation of its trypanothione reductase enzyme which neutralizes the reactive oxygen species generated inside the macrophages to kill the parasites...
May 2, 2018: Infectious Disorders Drug Targets
Philippe Holzmuller, Anne Geiger, Romaric Nzoumbou-Boko, Joana Pissarra, Sarra Hamrouni, Valérie Rodrigues, Frédéric-Antoine Dauchy, Jean-Loup Lemesre, Philippe Vincendeau, Rachel Bras-Gonçalves
Mononuclear phagocytes (monocytes, dendritic cells, and macrophages) are among the first host cells to face intra- and extracellular protozoan parasites such as trypanosomatids, and significant expansion of macrophages has been observed in infected hosts. They play essential roles in the outcome of infections caused by trypanosomatids, as they can not only exert a powerful antimicrobial activity but also promote parasite proliferation. These varied functions, linked to their phenotypic and metabolic plasticity, are exerted via distinct activation states, in which l-arginine metabolism plays a pivotal role...
2018: Frontiers in Immunology
Martin Golkowski, Gayani K Perera, Venkata Narayana Vidadala, Kayode K Ojo, Wesley C Van Voorhis, Dustin J Maly, Shao-En Ong
Glycogen synthase kinase 3 has evolutionarily conserved roles in cell signaling and metabolism and is a recognized drug target in neurological pathologies, most prominently bipolar disorder. More recently it has been suggested that GSK3 may be a target for the treatment of trypanosomatid parasite infections, e.g. with T. brucei, due to the lethal phenotype observed in parasite GSK3 short RNAi knockdown experiments. Here we investigated the kinome selectivity of a library of pyrrolo[3,4-c]pyrazol inhibitors that were developed against T...
February 12, 2018: Molecular omics
Marina Themoteo Varela, Joao Paulo S Fernandes
BACKGROUND: Neglected tropical diseases are a group of infections caused by microorganisms and viruses that affect mainly poor regions of the world. In addition, most available drugs are associated with long periods of treatment and high toxicity which limits the application and patient compliance. Investment in research and development is not seen as an attractive deal by the pharmaceutical industry since the final product must ideally be cheap, not returning the amount invested. Natural products have always played an important source for bioactive compounds and are advantageous over synthetic compounds when considering the unique structural variety and biological activities...
April 30, 2018: Current Medicinal Chemistry
Priscila Peña-Diaz, Jan Mach, Eva Kriegová, Pavel Poliak, Jan Tachezy, Julius Lukeš
Upon their translocation into the mitochondrial matrix, the N-terminal pre-sequence of nuclear-encoded proteins undergoes cleavage by mitochondrial processing peptidases. Some proteins require more than a single processing step, which involves several peptidases. Down-regulation of the putative Trypanosoma brucei mitochondrial intermediate peptidase (MIP) homolog by RNAi renders the cells unable to grow after 48 hours of induction. Ablation of MIP results in the accumulation of the precursor of the trypanosomatid-specific trCOIV protein, the largest nuclear-encoded subunit of the cytochrome c oxidase complex in this flagellate...
2018: PloS One
Ellen Schoener, Sarah Susanne Uebleis, Claudia Cuk, Michaela Nawratil, Adelheid G Obwaller, Thomas Zechmeister, Karin Lebl, Jana Rádrová, Carina Zittra, Jan Votýpka, Hans-Peter Fuehrer
Trypanosomatid flagellates have not been studied in Austria in any detail. In this study, specific nested PCR, targeted on the ribosomal small subunit, was used to determine the occurrence and diversity of trypanosomatids in wild-caught mosquitoes sampled across Eastern Austria in the years 2014-2015. We collected a total of 29,975 mosquitoes of 19 species divided in 1680 pools. Of these, 298 (17.7%), representing 12 different mosquito species, were positive for trypanosomatid DNA. In total, seven trypanosomatid spp...
2018: PloS One
Antoni R Blaazer, Abhimanyu Kumar Singh, Erik de Heuvel, Ewald Edink, Kristina M Orrling, Johan J N Veerman, Toine van den Bergh, Chimed Jansen, Erin Balasubramaniam, Wouter J Mooij, Hans Custers, Maarten Sijm, Daniel N A Tagoe, Titilola D Kalejaiye, Jane C Munday, Hermann Tenor, An Matheeussen, Maikel Wijtmans, Marco Siderius, Chris de Graaf, Louis Maes, Harry P de Koning, David S Bailey, Geert Jan Sterk, Iwan J P De Esch, David G Brown, Rob Leurs
Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, pharmacological evaluation, and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series...
April 19, 2018: Journal of Medicinal Chemistry
Flávia M Silva, Alexei Y Kostygov, Viktoria V Spodareva, Anzhelika Butenko, Regis Tossou, Julius Lukeš, Vyacheslav Yurchenko, João M P Alves
Trypanosomatids of the genera Angomonas and Strigomonas (subfamily Strigomonadinae) have long been known to contain intracellular beta-proteobacteria, which provide them with many important nutrients such as haem, essential amino acids and vitamins. Recently, Kentomonas sorsogonicus, a divergent member of Strigomonadinae, has been described. Herein, we characterize the genome of its endosymbiont, Candidatus Kinetoplastibacterium sorsogonicusi. This genome is completely syntenic with those of other known Ca...
April 12, 2018: Parasitology
Raoul De Gasparo, Elke Brodbeck-Persch, Steve Bryson, Nina B Hentzen, Marcel Kaiser, Emil F Pai, R Luise Krauth-Siegel, François Diederich
The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (Ki ) against Trypanosoma (T...
April 6, 2018: ChemMedChem
Letícia Marchese, Janaina de Freitas Nascimento, Flávia Silva Damasceno, Frédéric Bringaud, Paul A M Michels, Ariel Mariano Silber
Trypanosoma brucei , as well as Trypanosoma cruzi and more than 20 species of the genus Leishmania , form a group of flagellated protists that threaten human health. These organisms are transmitted by insects that, together with mammals, are their natural hosts. This implies that during their life cycles each of them faces environments with different physical, chemical, biochemical, and biological characteristics. In this work we review how amino acids are obtained from such environments, how they are metabolized, and how they and some of their intermediate metabolites are used as a survival toolbox to cope with the different conditions in which these parasites should establish the infections in the insects and mammalian hosts...
April 1, 2018: Pathogens
Carolina Bartolomé, María Buendía, María Benito, Pilar De la Rúa, Concepción Ornosa, Raquel Martín-Hernández, Mariano Higes, Xulio Maside
Trypanosomatids are highly prevalent pathogens of Hymenoptera; however, most molecular methods used to detect them in Apis and Bombus spp. do not allow the identification of the infecting species, which then becomes expensive and time consuming. To overcome this drawback, we developed a multiplex PCR protocol to readily identify in a single reaction the main trypanosomatids present in these hymenopterans (Lotmaria passim, Crithidia mellificae and Crithidia bombi), which will facilitate the study of their epidemiology and transmission dynamics...
March 30, 2018: Journal of Invertebrate Pathology
Julius Lukeš, Anzhelika Butenko, Hassan Hashimi, Dmitri A Maslov, Jan Votýpka, Vyacheslav Yurchenko
Trypanosomes and leishmanias are widely known parasites of humans. However, they are just two out of several phylogenetic lineages that constitute the family Trypanosomatidae. Although dixeny - the ability to infect two hosts - is a derived trait of vertebrate-infecting parasites, the majority of trypanosomatids are monoxenous. Like their common ancestor, the monoxenous Trypanosomatidae are mostly parasites or commensals of insects. This review covers recent advances in the study of insect trypanosomatids, highlighting their diversity as well as genetic, morphological and biochemical complexity, which, until recently, was underappreciated...
March 28, 2018: Trends in Parasitology
Florencia Díaz-Viraqué, María Laura Chiribao, Andrea Trochine, Fabiola González-Herrera, Christian Castillo, Ana Liempi, Ulrike Kemmerling, Juan Diego Maya, Carlos Robello
The discovery that trypanosomatids, unicellular organisms of the order Kinetoplastida, are capable of synthesizing prostaglandins raised questions about the role of these molecules during parasitic infections. Multiple studies indicate that prostaglandins could be related to the infection processes and pathogenesis in trypanosomatids. This work aimed to unveil the role of the prostaglandin F2 α synthase Tc OYE in the establishment of Trypanosoma cruzi infection, the causative agent of Chagas disease. This chronic disease affects several million people in Latin America causing high morbidity and mortality...
2018: Frontiers in Immunology
Amber D Tripodi, Allen L Szalanski, James P Strange
Crithidia bombi and Crithidia expoeki (Trypanosomatidae) are common parasites of bumble bees (Bombus spp.). Crithidia bombi was described in the 1980s, and C. expoeki was recently discovered using molecular tools. Both species have cosmopolitan distributions among their bumble bee hosts, but there have been few bumble bee studies that have identified infections to species since the original description of C. expoeki in 2010. Morphological identification of species is difficult due to variability within each stage of their complex lifecycles, although they can be easily differentiated through DNA sequencing...
March 14, 2018: Journal of Invertebrate Pathology
Godwin U Ebiloma, Evangelos Katsoulis, John O Igoli, Alexander I Gray, Harry P De Koning
Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-α-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ≥ EC50 (0.4 μg/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1 h). Fluorescence microscopic assessment of DNA configuration revealed severe cell cycle defects after 8 h of incubation with the compound, the equivalent of a single generation time...
March 15, 2018: Scientific Reports
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