Biochemical composition and metabolic pathways of filarial worms Setaria cervi: search for new antifilarial agents

AbstractThe main problem regarding the chemotherapy of filariasis is that no safe and effective drug is available yet to combat the adult human filarial worms. Setaria cervi, the causal organism of setariasis and lumbar paralysis in cattle, is routinely employed as a model organism for conducting biochemical and enzymatic studies on filarial parasites. In view of the practical difficulties in procuring human strains of Wuchereria bancrofti and Brugia malayi for drug screening, the bovine filarial parasite S. cervi, resembling the human species in having microfilarial periodicity and chemotherapeutic response to known antifilarial agents, is widely used as a model in such studies. For a rational approach to antifilarial chemotherapy, knowledge of the biochemical composition and metabolic pathways of this helminth parasite may be of paramount importance, so that more potent antifilarial agents based on specific drug targets can be identified in drug discovery programmes. The present review provides an update on the biochemistry of the important metabolic pathways functioning within this potentially important bovine parasite, that have so far been studied, and on those that need to be investigated further so as to identify novel drug targets that can be exploited for designing new antifilarial drugs.

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Reconstruction of Sugar Metabolic Pathways of Giardia lamblia

International Journal of Proteomics ◽

10.1155/2012/980829 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Jian Han ◽

Lesley J. Collins

Keyword(s):

Giardia Lamblia ◽

Metabolic Pathways ◽

Drug Targets ◽

Sugar Metabolism ◽

Tca Cycle ◽

The Tca Cycle ◽

Glycolysis Pathway ◽

Bioinformatic Approaches ◽

Novel Drug ◽

Novel Drug Targets

Giardia lamblia is an “important” pathogen of humans, but as a diplomonad excavate it is evolutionarily distant from other eukaryotes and relatively little is known about its core metabolic pathways. KEGG, the widely referenced site for providing information of metabolism, does not yet include many enzymes from Giardia species. Here we identify Giardia’s core sugar metabolism using standard bioinformatic approaches. By comparing Giardia proteomes with known enzymes from other species, we have identified enzymes in the glycolysis pathway, as well as some enzymes involved in the TCA cycle and oxidative phosphorylation. However, the majority of enzymes from the latter two pathways were not identifiable, indicating the likely absence of these functionalities. We have also found enzymes from the Giardia glycolysis pathway that appear more similar to those from bacteria. Because these enzymes are different from those found in mammals, the host organisms for Giardia, we raise the possibility that these bacteria-like enzymes could be novel drug targets for treating Giardia infections.

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Construction of Metabolic Pathways based on Whole Genome Sequencing Reveals Laterally- Transferred Wolbachia-like Sequences in the Setaria Digitata Genome

10.21203/rs.3.rs-579175/v1 ◽

2021 ◽

Author(s):

Nadarajah Rashanthy ◽

Mahil Sharada Alwis Kothalawala ◽

Thamarahansi Shashiprabha Mugunamalwaththa ◽

Kasun de Zoysa ◽

Naduviladath Vishvanath Chandrasekharan ◽

...

Keyword(s):

Metabolic Pathways ◽

Functional Annotation ◽

Sequence Similarity ◽

Draft Genome ◽

Model Organism ◽

Animal Husbandry ◽

Wuchereria Bancrofti ◽

Economic Losses ◽

Whole Genome ◽

Setaria Digitata

Abstract Setaria digitata is a Wolbachia-free filarial parasite that causes cerebrospinal nematodiasis in non-permissive hosts such as goats, sheep and horses leading to substantial economic losses in animal husbandry. Due to its similarity to Wuchereria bancrofti, primary causing agent of human lymphatic filariasis (HLF), S. digitata can be used as a model organism to study the biology of HLF. This study was mainly aimed to bring functional analysis of metabolic pathways in S. digitata. A draft genome of 78,774,594 bases making a total of 2,075 contigs was generated. ‘BLAST2GO’ functional annotation resulted in 28112 BLAST hits with an e-value lower than 1e-4 and a sequence similarity higher than 30%. Out of a total of 2075 contigs, 1280 contigs were used to generate a total of 6055 GO annotations at a mean level of 6.488 with standard deviation of 2.675. Overall, 89.1% of mapped reads were annotated by at least one of the three categories of the GO function classification. Moreover, 111 enzymes associated with 95 distinct metabolic pathways were identified. We suggest that S. digitata may have evolved its own sequences to code for haem, riboflavin, and FAD in the absence of Wolbachia.

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Subtractive Genomics Approach for Identification of Novel Therapeutic Drug Targets in Mycoplasma genitalium

Pathogens ◽

10.3390/pathogens10080921 ◽

2021 ◽

Vol 10 (8) ◽

pp. 921

Author(s):

Abiodun Joseph Fatoba ◽

Moses Okpeku ◽

Matthew Adekunle Adeleke

Keyword(s):

Metabolic Pathways ◽

Drug Targets ◽

Mycoplasma Genitalium ◽

Therapeutic Drug ◽

Homologous Proteins ◽

Subtractive Genomics ◽

Cytoplasmic Proteins ◽

Novel Drug ◽

Novel Drug Targets ◽

Novel Therapeutic

Mycoplasma genitalium infection is a sexually transmitted infection that causes urethritis, cervicitis, and pelvic inflammatory disease (PID) in men and women. The global rise in antimicrobial resistance against recommended antibiotics for the treatment of M. genitalium infection has triggered the need to explore novel drug targets against this pathogen. The application of a bioinformatics approach through subtractive genomics has proven highly instrumental in predicting novel therapeutic targets against a pathogen. This study aimed to identify essential and non-homologous proteins with unique metabolic pathways in the pathogen that could serve as novel drug targets. Based on this, a manual comparison of the metabolic pathways of M. genitalium and the human host was done, generating nine pathogen-specific metabolic pathways. Additionally, the analysis of the whole proteome of M. genitalium using different bioinformatics databases generated 21 essential, non-homologous, and cytoplasmic proteins involved in nine pathogen-specific metabolic pathways. The further screening of these 21 cytoplasmic proteins in the DrugBank database generated 13 druggable proteins, which showed similarity with FDA-approved and experimental small-molecule drugs. A total of seven proteins that are involved in seven different pathogen-specific metabolic pathways were finally selected as novel putative drug targets after further analysis. Therefore, these proposed drug targets could aid in the design of potent drugs that may inhibit the functionality of these pathogen-specific metabolic pathways and, as such, lead to the eradication of this pathogen.

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The Genome of Setaria digitata: A Cattle Nematode Closely Related to Human Filarial Parasites

Genome Biology and Evolution ◽

10.1093/gbe/evaa017 ◽

2020 ◽

Vol 12 (2) ◽

pp. 3971-3976

Author(s):

Kanchana S Senanayake ◽

Jonas Söderberg ◽

Aleksei Põlajev ◽

Maja Malmberg ◽

Eric H Karunanayake ◽

...

Keyword(s):

Developing Countries ◽

Lymphatic Filariasis ◽

Genome Sequence ◽

Drug Targets ◽

Parasitic Nematode ◽

Draft Genome ◽

Model Organism ◽

Wuchereria Bancrofti ◽

Setaria Digitata ◽

Novel Drugs

Abstract Here we present the draft genome sequence of Setaria digitata, a parasitic nematode affecting cattle. Due to its similarity to Wuchereria bancrofti, the parasitic nematode that causes lymphatic filariasis in humans, S. digitata has been used as a model organism at the genomic level to find drug targets which can be used for the development of novel drugs and/or vaccines for human filariasis. Setaria digitata causes cerebrospinal nematodiasis in goats, sheep, and horses posing a serious threat to livestock in developing countries. The genome sequence of S. digitata will assist in finding candidate genes to use as drug targets in both S. digitata and W. bancrofti. The assembled draft genome is ∼90 Mb long and contains 8,974 genomic scaffolds with a G+C content of 31.73%.

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Prediction of Novel Drug Targets and Vaccine Candidates against Human Lice (Insecta), Acari (Arachnida), and Their Associated Pathogens

Vaccines ◽

10.3390/vaccines10010008 ◽

2021 ◽

Vol 10 (1) ◽

pp. 8

Author(s):

Abid Ali ◽

Shabir Ahmad ◽

Pedro Machado Medeiros de Albuquerque ◽

Atif Kamil ◽

Fahdah Ayed Alshammari ◽

...

Keyword(s):

Metabolic Pathways ◽

Drug Targets ◽

Babesia Microti ◽

Economic Losses ◽

Borrelia Miyamotoi ◽

Vaccine Candidates ◽

Essential Proteins ◽

Membrane Bound ◽

Novel Drug ◽

Novel Drug Targets

The emergence of drug-resistant lice, acari, and their associated pathogens (APs) is associated with economic losses; thus, it is essential to find new appropriate therapeutic approaches. In the present study, a subtractive proteomics approach was used to predict suitable therapeutics against these vectors and their infectious agents. We found 9701 proteins in the lice (Pediculus humanus var. corporis) and acari (Ixodes scapularis, Leptotrombidium deliense), and 4822 proteins in the proteomes of their APs (Babesia microti, Borreliella mayonii, Borrelia miyamotoi, Borrelia recurrentis, Rickettsia prowazekii, Orientia tsutsugamushi str. Boryong) that were non-homologous to host proteins. Among these non-homologous proteins, 365 proteins of lice and acari, and 630 proteins of APs, were predicted as essential proteins. Twelve unique essential proteins were predicted to be involved in four unique metabolic pathways of lice and acari, and 103 unique proteins were found to be involved in 75 unique metabolic pathways of APs. The sub cellular localization analysis of 115 unique essential proteins of lice and acari and their APs revealed that 61 proteins were cytoplasmic, 42 as membrane-bound proteins and 12 proteins with multiple localization. The druggability analysis of the identified 73 cytoplasmic and multiple localization essential proteins revealed 22 druggable targets and 51 novel drug targets that participate in unique pathways of lice and acari and their APs. Further, the predicted 42 membrane bound proteins could be potential vaccine candidates. Screening of useful inhibitors against these novel targets may result in finding novel compounds efficient for the control of these parasites.

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Metabolic Pathways as Drug Targets: Targeting the Sulphur Assimilatory Pathways of Yeast and Fungi for Novel Drug Discovery

Combating Fungal Infections ◽

10.1007/978-3-642-12173-9_14 ◽

2010 ◽

pp. 327-346 ◽

Cited By ~ 4

Author(s):

Anand Kumar Bachhawat ◽

Amit Kumar Yadav

Keyword(s):

Drug Discovery ◽

Metabolic Pathways ◽

Drug Targets ◽

Novel Drug

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IN SILICO IDENTIFICATION OF NOVEL DRUG TARGETS IN ACINETOBACTER BAUMANNII BY SUBTRACTIVE GENOMIC APPROACH

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i3.22105 ◽

2018 ◽

Vol 11 (3) ◽

pp. 230 ◽

Cited By ~ 3

Author(s):

Meenu Goyal ◽

Citu Citu ◽

Nidhi Singh

Keyword(s):

Acinetobacter Baumannii ◽

In Silico ◽

Metabolic Pathways ◽

Drug Targets ◽

Potential Drug ◽

Homologous Proteins ◽

Essential Proteins ◽

Novel Drug ◽

Potential Drug Targets ◽

Novel Drug Targets

Objective: Multiple drug resistance (MDR) in bacteria, particularly Gram-negative bacilli, has significantly hindered the treatment of infections caused by these bacteria. This results in the need for identifying new drugs and drug targets for these bacteria. The objective of this study was to identify novel drug targets in Acinetobacter baumannii which has emerged as a medically important pathogen due to an increasing number of infections caused by it and its MDR property.Methods: In our study, we implemented in silico subtractive genomics approach to identify novel drug targets in A. baumannii American type culture collection 17978. Various databases and online software were used to build a systematic workflow involving comparative genomics, metabolic pathways analysis, and drug target prioritization to identify pathogen-specific novel drug targets.Results: First, 458 essential proteins were retrieved from a database of essential genes, and by performing BLASTp against Homo sapiens, 246 human non-homologous essential proteins were selected of 458 proteins. Metabolic pathway analysis performed by Kyoto Encyclopedia of Genes and Genomes–Kyoto Automatic Annotation Server revealed that these 246 essential non-homologous proteins were involved in 66 metabolic pathways. Among these metabolic pathways, 12 pathways were found to be unique to Acinetobacter that involved 37 non-homologous essential proteins. Of these essential non-homologous proteins, 19 proteins were found in common as well as unique metabolic pathways and only 18 proteins were unique to Acinetobacter. Finally, these target proteins were filtered to 9 potential targets, based on subcellular localization and assessment of druggability using Drug bank, ChEMBL, and literature.Conclusion: Our study identified nine potential drug targets which are novel targets in A. baumannii and can be used for designing drugs against these proteins. These drugs will be pathogen specific with no side effects on human host, as the potential drug targets are human non-homologous.

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