Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

The filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae—which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

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Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

10.1101/767798 ◽

2019 ◽

Author(s):

DM Curran ◽

A Grote ◽

N Nursimulu ◽

A Geber ◽

D Voronin ◽

...

Keyword(s):

Drug Targets ◽

Metabolic Networks ◽

Metabolic Model ◽

Endosymbiotic Bacteria ◽

Parasitic Worm ◽

Eukaryotic Organisms ◽

New Treatments ◽

Genome Scale ◽

Novel Drug ◽

Novel Drug Targets

AbstractThe filarial nematodeBrugia malayirepresents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteriaWolbachia—present in many filariae—which is vital to the worm.Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but only recently have been applied to eukaryotic organisms. Here, we presentiDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 99 reactions essential to the survival ofB. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

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Using a Genome-Scale Metabolic Model of Enterococcus faecalis V583 To Assess Amino Acid Uptake and Its Impact on Central Metabolism

Applied and Environmental Microbiology ◽

10.1128/aem.03279-14 ◽

2014 ◽

Vol 81 (5) ◽

pp. 1622-1633 ◽

Cited By ~ 18

Author(s):

Nadine Veith ◽

Margrete Solheim ◽

Koen W. A. van Grinsven ◽

Brett G. Olivier ◽

Jennifer Levering ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Metabolic Network ◽

Drug Targets ◽

Metabolic Model ◽

Content Type ◽

A Genome ◽

Genome Scale ◽

Novel Drug ◽

Novel Drug Targets

ABSTRACTIncreasing antibiotic resistance in pathogenic bacteria necessitates the development of new medication strategies. Interfering with the metabolic network of the pathogen can provide novel drug targets but simultaneously requires a deeper and more detailed organism-specific understanding of the metabolism, which is often surprisingly sparse. In light of this, we reconstructed a genome-scale metabolic model of the pathogenEnterococcus faecalisV583. The manually curated metabolic network comprises 642 metabolites and 706 reactions. We experimentally determined metabolic profiles ofE. faecalisgrown in chemically defined medium in an anaerobic chemostat setup at different dilution rates and calculated the net uptake and product fluxes to constrain the model. We computed growth-associated energy and maintenance parameters and studied flux distributions through the metabolic network. Amino acid auxotrophies were identified experimentally for model validation and revealed seven essential amino acids. In addition, the important metabolic hub of glutamine/glutamate was altered by constructing a glutamine synthetase knockout mutant. The metabolic profile showed a slight shift in the fermentation pattern toward ethanol production and increased uptake rates of multiple amino acids, especiallyl-glutamine andl-glutamate. The model was used to understand the altered flux distributions in the mutant and provided an explanation for the experimentally observed redirection of the metabolic flux. We further highlighted the importance of gene-regulatory effects on the redirection of the metabolic fluxes upon perturbation. The genome-scale metabolic model presented here includes gene-protein-reaction associations, allowing a further use for biotechnological applications, for studying essential genes, proteins, or reactions, and the search for novel drug targets.

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