Modelling parasitic worm metabolism suggests strategy for developing new
drugs against infection

Date:
August 11, 2020
Source:
eLife
Summary:
Scientists have revealed a way to eradicate parasitic worms by
stopping them from using alternative metabolism pathways provided
by bacteria that live within them, according to new findings.



FULL STORY ========================================================================== Scientists have revealed a way to eradicate parasitic worms by stopping
them from using alternative metabolism pathways provided by bacteria
that live within them, according to new findings published today in eLife.


==========================================================================
The study has identified three potential drugs that are active against the parasitic worm Brugia malayi (B. malayi), a leading cause of disability
in the developing world.

Latest figures from 2015 suggest an estimated 40 million people in the
world have lymphatic filariasis (elephantiatis) caused by worms such
as B. malayi, with an estimated one billion people at risk. Current
prevention and treatment efforts rely on a small selection of drugs,
but these have limited effectiveness and must be taken for 15 years,
and there is an emerging threat of drug resistance.

"One alternative strategy for preventing lymphatic filariasis has been
to use traditional antibiotics to target bacteria that live within most filarial worms," explains lead author David Curran, Research Associate
at the Hospital for Sick Children (SickKids) in Toronto, Canada. "These bacteria, from the genus Wolbachia, are specific to each worm and are
known to be essential for the worms to survive and reproduce." While
targeting the Wolbachia bacteria with antibiotics is a viable strategy,
Curran adds that long treatment times and the unsuitability of these antibiotics for pregnant women and children prevent their widespread
use, and there remains an urgent need to identify novel targets for
treatments. In this study, he and his colleagues looked at targeting
both the worm and the bacteria by identifying the essential biological processes provided by the bacteria that the worm depends on.

To do this, they built a model of all the metabolic pathways that take
place in the worm and in its resident bacteria. They then systematically changed different components of the model, such as oxygen levels,
glucose levels, and which enzymes were activated, to see the effects on
the worm's growth. Their final model included 1,266 metabolic reactions involving 1,252 metabolites and 1,011 enzymes linked to 625 genes.

To cope with the different nutrient conditions, the worm adapted its
use of different metabolic pathways -- including those provided by the Wolbachia bacteria -- throughout the different stages of its lifecycle. To
see which of the metabolic reactions were critical for survival and reproduction, the team removed some of the possible pathways from the
model. They identified 129 metabolic reactions that slowed the growth
to less than 50% of the baseline level. Of these, 50 were metabolic
processes provided by the Wolbachia bacteria.

Having identified these essential metabolic reactions, the team searched
for drugs that could block crucial molecules involved in activating these reactions, using databases of existing drugs and their targets. They
identified three drugs: fosmidomycin, an antibiotic and potential
antimalarial drug; MDL- 29951, a treatment being tested for epilepsy and diabetes; and tenofovir, which is approved for treating hepatitis B and
HIV. These drugs reduced the numbers of Wolbachia bacteria per worm by
53%, 24% and 30%, respectively.

"We also found that two of the drugs, fosmidomycin and tenofovir, reduced
the worm's reproductive ability," explains co-senior author Elodie Ghedin, previously Professor of Biology and Professor of Epidemiology at New York University, and now Senior Investigator at the National Institutes of
Health, Maryland, US. "Fosmidomycin also appeared to affect movement in
the worms." "All three of the drugs tested appear to act against adult
B. malayi worms by affecting the metabolism of the worms themselves or
their resident bacteria," concludes co-senior author John Parkinson,
Senior Scientist, Molecular Medicine program, SickKids, and Associate Professor, Biochemistry & Molecular and Medical Genetics, University of Toronto. "This validates our model as a realistic construction of the
metabolic processes in these debilitating parasites, and suggests that
its use may yield further therapeutic targets with more research."

========================================================================== Story Source: Materials provided by eLife. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. David M Curran, Alexandra Grote, Nirvana Nursimulu, Adam Geber,
Dennis
Voronin, Drew R Jones, Elodie Ghedin, John Parkinson. Modeling
the metabolic interplay between a parasitic worm and its bacterial
endosymbiont allows the identification of novel drug targets. eLife,
2020; 9 DOI: 10.7554/eLife.51850 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200811120101.htm

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