scholarly journals Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

2021 ◽  
Vol 17 (12) ◽  
pp. e1010124
Author(s):  
Laura E. de Vries ◽  
Matteo Lunghi ◽  
Aarti Krishnan ◽  
Taco W. A. Kooij ◽  
Dominique Soldati-Favre
Keyword(s):  
Drug Targets ◽  
Parasite Species ◽  
Life Cycles ◽  
Biosynthetic Pathways ◽  
Preclinical Development ◽  
Critical Pathways ◽  
Alternative Pathways ◽  
Antiparasitic Drug ◽  
Vitamin B5 ◽  
Antiparasitic Drugs

The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.

Speciation of cestoda. Evidence for two sibling species in the complex Bothrimonus nylandicus (Schneider 1902) (Cestoda: Cyathocephalidea)

Parasitology ◽  
1988 ◽  
Vol 97 (1) ◽  
pp. 139-147 ◽  
Author(s):  
F. Renaud ◽  
C. Gabrion
Keyword(s):  
Sibling Species ◽  
Definitive Host ◽  
Parasite Species ◽  
Adult Stage ◽  
Life Cycles ◽  
The Other ◽  
Congeneric Species ◽  
Biochemical Genetic ◽  
Autumn And Winter ◽  
Biological Differences

SUMMARYUsing biochemical genetic methods, we have distinguished 2 sibling species in the complex Bothrimonus nylandicus (Schneider, 1902), which infest 2 congeneric species of sole (Solea lascaris and Solea impar) on European coasts (Atlantic and Mediterranean). Neither of the parasite species is specific for either of the sole species, but one of them is present all year round, whereas the other is absent in the autumn and winter and only appears in the spring, subsequently disappearing at the end of the summer. Only S. impar lives in the Mediterranean, and is equally infested by both cestodes, whereas both species occur in the Atlantic and each of them is preferentially infested by 1 species of cestode. The shortness of the adult stage of the parasite in the definitive host and the presence of 2 life-cycles associated with competition between the 2 hosts in the Atlantic could be responsible for the biological differences observed and for maintaining the sibling species in sympatry.

scholarly journals Alternative pathways of zeaxanthin biosynthesis in a Flavobacterium species. Experiments with nicotine as inhibitor

1974 ◽  
Vol 144 (2) ◽  
pp. 231-243 ◽  
Author(s):  
J C B McDermott ◽  
D J Brown ◽  
G Britton ◽  
T W Goodwin
Keyword(s):  
Cyclization Reaction ◽  
Biosynthetic Pathways ◽  
Anaerobic Conditions ◽  
Anaerobic Process ◽  
Alternative Pathways ◽  
Nicotine Concentration ◽  
Β Carotene

In Flavobacterium R1519, nicotine blocks zeaxanthin biosynthesis by specifically inhibiting the cyclization reaction. Lycopene (at high nicotine concentrations, e.g. 7.5mm) and rubixanthin (at low nicotine concentration, e.g. 1mm) replace zeaxanthin as the main carotenoid. On removal of the nicotine lycopene is converted into β-carotene under anaerobic conditions and into zeaxanthin in the presence of O2. The conversion in vivo of β-carotene into zeaxanthin was also demonstrated. Cyclization (an anaerobic process) thus precedes hydroxylation (O2-requiring) in the biosynthesis of zeaxanthin. The conversion in vivo of rubixanthin into β-cryptoxanthin and into zeaxanthin was demonstrated, thus indicating the operation of alternative pathways of zeaxanthin biosynthesis. Several alternative biosynthetic pathways are considered and the results are also discussed in terms of reaction sequences of carotenoid ‘half-molecules’.

Investigating the Role of Inflammasome Caspases 1 and 11 in the Acute Radiation Syndrome

2021 ◽  
Author(s):  
Andrea R. Daniel ◽  
Lixia Luo ◽  
Chang-Lung Lee ◽  
David G. Kirsch
Keyword(s):  
Cell Death ◽  
Drug Targets ◽  
Acute Radiation ◽  
Rational Approach ◽  
High Dose ◽  
Acute Radiation Syndrome ◽  
Alternative Pathways ◽  
Caspase 1 ◽  
Organ Systems ◽  
Sensitive Organ

Exposure to high dose radiation causes life-threatening acute and delayed effects. Defining the mechanisms of lethal radiation-induced acute toxicity of gastrointestinal and hematopoietic tissues are critical steps to identify drug targets to mitigate and protect against the acute radiation syndrome (ARS). For example, one rational approach would be to design pharmaceuticals that block cell death pathways to preserve tissue integrity in radiation-sensitive organ systems including the gastrointestinal tract and hematopoietic compartment. A previous study reported that the inflammasome pathway, which mediates inflammatory cell death through pyroptosis, promotes ARS. However, we show that mice lacking the inflammatory executioner caspases, caspase-1 and caspase-11, are not protected from ARS when compared directly to littermates expressing caspase-1 and caspase-11. These results suggest that alternative pathways will need to be targeted by drugs that successfully mitigate and protect against the ARS.

scholarly journals Evolution of alternative biosynthetic pathways for vitamin C following plastid acquisition in photosynthetic eukaryotes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Glen Wheeler ◽  
Takahiro Ishikawa ◽  
Varissa Pornsaksit ◽  
Nicholas Smirnoff
Keyword(s):  
Vitamin C ◽  
Biosynthetic Pathway ◽  
Critical Role ◽  
Biosynthetic Pathways ◽  
Oxygen Species ◽  
Photosynthetic Eukaryote ◽  
Alternative Pathways ◽  
Photosynthetic Eukaryotes ◽  
Gulonolactone Oxidase ◽  
Eukaryote Evolution

Ascorbic acid (vitamin C) is an enzyme co-factor in eukaryotes that also plays a critical role in protecting photosynthetic eukaryotes against damaging reactive oxygen species derived from the chloroplast. Many animal lineages, including primates, have become ascorbate auxotrophs due to the loss of the terminal enzyme in their biosynthetic pathway, l-gulonolactone oxidase (GULO). The alternative pathways found in land plants and Euglena use a different terminal enzyme, l-galactonolactone dehydrogenase (GLDH). The evolutionary processes leading to these differing pathways and their contribution to the cellular roles of ascorbate remain unclear. Here we present molecular and biochemical evidence demonstrating that GULO was functionally replaced with GLDH in photosynthetic eukaryote lineages following plastid acquisition. GULO has therefore been lost repeatedly throughout eukaryote evolution. The formation of the alternative biosynthetic pathways in photosynthetic eukaryotes uncoupled ascorbate synthesis from hydrogen peroxide production and likely contributed to the rise of ascorbate as a major photoprotective antioxidant.

scholarly journals Computational Identification of Metabolic Pathways ofPlasmodium falciparumusing thek-Shortest Path Algorithm

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Jelili Oyelade ◽  
Itunuoluwa Isewon ◽  
Olufemi Aromolaran ◽  
Efosa Uwoghiren ◽  
Titilope Dokunmu ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Shortest Path ◽  
Metabolic Pathways ◽  
Drug Targets ◽  
Poor Response ◽  
Metabolic Model ◽  
Pentose Phosphate ◽  
Shortest Path Algorithm ◽  
Alternative Pathways ◽  
Essential Reactions

Plasmodium falciparum, a malaria pathogen, has shown substantial resistance to treatment coupled with poor response to some vaccines thereby requiring urgent, holistic, and broad approach to prevent this endemic disease. Understanding the biology of the malaria parasite has been identified as a vital approach to overcome the threat of malaria. This study is aimed at identifying essential proteins unique to malaria parasites using a reconstructediPfagenome-scale metabolic model (GEM) of the 3D7 strain ofPlasmodium falciparumby filling gaps in the model with nineteen (19) metabolites and twenty-three (23) reactions obtained from the MetaCyc database. Twenty (20) currency metabolites were removed from the network because they have been identified to produce shortcuts that are biologically infeasible. The resulting modifiediPfaGEM was a model using thek-shortest path algorithm to identify possible alternative metabolic pathways in glycolysis and pentose phosphate pathways ofPlasmodium falciparum. Heuristic function was introduced for the optimal performance of the algorithm. To validate the prediction, the essentiality of the reactions in the reconstructed network was evaluated using betweenness centrality measure, which was applied to every reaction within the pathways considered in this study. Thirty-two (32) essential reactions were predicted among which our method validated fourteen (14) enzymes already predicted in the literature. The enzymatic proteins that catalyze these essential reactions were checked for homology with the host genome, and two (2) showed insignificant similarity, making them possible drug targets. In conclusion, the application of the intelligent search technique to the metabolic network ofP. falciparumpredicts potential biologically relevant alternative pathways using graph theory-based approach.

Effect In Vitro of Antiparasitic Drugs on Microbial Inhibitor Test Responses for Screening Antibiotic Residues in Goat's Milk

2015 ◽  
Vol 78 (9) ◽  
pp. 1756-1759 ◽  
Author(s):  
T. ROMERO ◽  
M. C. BELTRÁN ◽  
W. REYBROECK ◽  
M. P. MOLINA
Keyword(s):  
Antibiotic Residues ◽  
Goat’S Milk ◽  
Drug Concentrations ◽  
Test Microorganism ◽  
Antiparasitic Drug ◽  
Goat's Milk ◽  
Antiparasitic Drugs ◽  
Almost All ◽  
Positive Results

Microbial inhibitor tests are widely used to screen antibiotic residues in milk; however, these tests are nonspecific and may be affected by various substances capable of inhibiting the growth of the test microorganism. The objective of this study was to determine the effect of antiparasitic drugs in goat's milk on the microbial inhibitor test response. Raw antibiotic-free milk from Murciano-Granadina goats was supplemented with eight concentrations of seven antiparasitic substances (albendazole, 10 to 170 mg/kg; closantel, 1 to 140 mg/kg; diclazuril, 8 to 45 mg/kg; febendazole, 10 to 140 mg/kg; levamisole, 40 to 440 mg/kg; diazinon, 8 to 45 mg/kg; and ivermectin, 40 to 200 mg/kg). Twelve replicates for each concentration were analyzed with three microbial inhibitor tests: BRT MRL, Delvotest SP-NT MSC, and Eclipse 100. The results were interpreted visually (negative or positive). Using a logistic regression model, the concentrations of the antiparasitic drugs producing 5% (IC5), 10% (IC10), and 50% (IC50) positive results were determined. In general, the Eclipse 100 test was less sensitive to the effect of antiparasitic substances; the inhibitory concentrations of almost all the drugs assayed were higher than those for other tests. Conversely, the BRT MRL test was most affected, with high levels of interference at lower antiparasitic drug concentrations. Closantel and diazinon interfered with all microbial tests at lower concentrations than did other drugs (IC5 = 1 to 26 and 12 to 20 mg/kg, respectively), and higher concentrations of levamisole and diclazuril (IC5 = 30 to 240 and 50 to 117 mg/kg, respectively) were required to produce 5% positive results. These findings indicate that microbial inhibitor tests can be affected by elevated concentrations of antiparasitic drugs in goat's milk.

Checklist of the parasites of the black-necked swan, Cygnus melanocoryphus (Aves: Anatidae), with new records from Chile

Zootaxa ◽  
2010 ◽  
Vol 2637 (1) ◽  
pp. 55 ◽  
Author(s):  
DANIEL GONZÁLEZ-ACUÑA ◽  
LUCILA MORENO ◽  
ARMANDO CICCHINO ◽  
SERGEY MIRONOV ◽  
MIKE KINSELLA
Keyword(s):  
South America ◽  
Parasite Species ◽  
New Records ◽  
Southern Cone ◽  
Life Cycles ◽  
Intermediate Hosts ◽  
New Host ◽  
Echinostoma Trivolvis ◽  
New Host Records

Black-necked swans (Cygnus melanocoryphus) are endemic to the southern cone of South America. Their range extends from Brazil and Paraguay south to Argentina and Chile. A total of 16 parasite species were collected from 7 swans from the Biobio region, Chile, of which 12 are new records for Chile and 11 represent new host records, Echinostoma trivolvis, Paranomostomum sp., Microsomacanthus sp., Nadejdolepis sp., Retinometra sp., Avioserpens sp., Capillaria skrjabini, Ingrassia cygni, Anatoecus penicillatus, A. icterodes and A. keymeri. A checklist is presented that summarizes sites of infections, localities, life cycles and their intermediate hosts (if known), and the pertinent references to demonstrate the wide diversity of parasites of black-necked swans. Our review of the existing literature (23 publications) along with our own records provided information on a total of 18 families and 27 genera, including 33 described species (some only identified to genus), of which 11 were recorded only in Chile (8 endoparasites and 3 ectoparasites), and 6 only in Argentina (4 endoparasites and 2 ectoparasites). Five parasites are known only from captive swans in European zoos. Parasites recorded from C. melanocoryphus include 23 helminths and 10 ectoparasites (one leech and 9 arthropods).

Membrane lipidomics for the discovery of new antiparasitic drug targets

2011 ◽  
Vol 27 (11) ◽  
pp. 496-504 ◽  
Author(s):  
Eric Maréchal ◽  
Mickaël Riou ◽  
Dominique Kerboeuf ◽  
Frédéric Beugnet ◽  
Pierre Chaminade ◽  
...  
Keyword(s):  
Drug Targets ◽  
Antiparasitic Drug

scholarly journals A brief review on the mode of action of antinematodal drugs

2017 ◽  
Vol 67 (2) ◽  
pp. 137-152 ◽  
Author(s):  
Melanie Abongwa ◽  
Richard J. Martin ◽  
Alan P. Robertson
Keyword(s):  
Drug Resistance ◽  
Mode Of Action ◽  
Drug Targets ◽  
Parasite Species ◽  
Effective Control ◽  
Macrocyclic Lactones ◽  
Resistance Development ◽  
Cholinergic Agonists ◽  
Nematode Parasites ◽  
Parasite Populations

Abstract Anthelmintics are some of the most widely used drugs in veterinary medicine. Here we review the mechanism of action of these compounds on nematode parasites. Included are the older classes of compounds; the benzimidazoles, cholinergic agonists and macrocyclic lactones. We also consider newer anthelmintics, including emodepside, derquantel and tribendimidine. In the absence of vaccines for most parasite species, control of nematode parasites will continue to rely on anthelmintic drugs. As a consequence, vigilance in detecting drug resistance in parasite populations is required. Since resistance development appears almost inevitable, there is a continued and pressing need to fully understand the mode of action of these compounds. It is also necessary to identify new drug targets and drugs for the continued effective control of nematode parasites.

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