Researchers develop new drugs to eradicate parasitic worms

A team of researchers has now demonstrated a novel method to eliminate parasitic worms. In this breakthrough method, parasitic worms are prevented from using alternative metabolism routes offered by microbes living inside them.

The study results were recently published in the eLife journal.

The researchers discovered three promising drugs that are active against Brugia malayi (B. malayi)—a type of parasitic worm that is mainly responsible for causing disability in the developing world.

According to the latest figures from 2015, approximately 40 million individuals in the world are estimated to have lymphatic filariasis, or elephantiasis, which is caused by worms like B. malayi. Moreover, an estimated one billion individuals are at risk of developing this disability.

Existing prevention and treatment efforts largely depend on an insignificant selection of medications, but such drugs are not highly effective and should be taken for as long as 15 years, and added to this, there is a growing 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. These bacteria, from the genus Wolbachia, are specific to each worm and are known to be essential for the worms to survive and reproduce.”

David Curran, Study Lead Author and Research Associate, Hospital for Sick Children

According to Curran, while it is a viable strategy to target the Wolbachia bacteria with antibiotics, extended treatment times and the inappropriateness of such antibiotics for children and pregnant women prevent their extensive use; hence, there is still an urgent need to detect new targets for treatments.

In this research, Curran and his collaborators explored the option of targeting both the bacteria and the worm by detecting the crucial biological processes offered by the microbes. The worm relies on such biological processes.

To achieve this, the researchers developed a model of all the metabolic routes that occur in the worm and also in the bacteria residing within it. Then, they methodically altered different parts of the model, like glucose levels, oxygen levels, and the types of enzymes that were stimulated, to observe the impacts on the growth of the worm.

The team’s ultimate model included as many as 1,266 metabolic reactions involving 1,011 enzymes and 1,252 metabolites associated with 625 genes.

To deal with the varying nutrient conditions, the worm modified its use of different metabolic routes—such as those offered by the Wolbachia bacteria—all through the different phases of its lifecycle.

To observe which of the metabolic reactions were actually crucial for both reproduction and survival, the researchers eliminated a few potential pathways from the model. They detected a total of 129 metabolic reactions that decreased the growth to below 50% of the baseline level. Among these, 50 reactions were metabolic processes offered by the Wolbachia bacteria.

After detecting these crucial metabolic reactions, the researchers used databases of prevalent drugs and their targets and eventually looked for drugs that can potentially inhibit vital molecules that are implicated in triggering these reactions.

They eventually detected three kinds of drugs—MDL-29951, a treatment being examined for diabetes and epilepsy; fosmidomycin, an antibiotic and promising antimalarial drug; and tenofovir, which has been approved for treating HIV and hepatitis B.

Such drugs decreased the numbers of Wolbachia bacteria for each worm by 24%, 53%, and 30%, in that order.

We also found that two of the drugs, fosmidomycin and tenofovir, reduced the worm’s reproductive ability. Fosmidomycin also appeared to affect movement in the worms.”

Elodie Ghedin, Study Co-Senior Author and Senior Investigator, National Institutes of Health, Maryland, US

Previously, Ghedin served as a Professor of Biology and Professor of Epidemiology in the New York University.

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. 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.”

John Parkinson, Study Co-Senior Author and Senior Scientist, Molecular Medicine Program, SickKids

Parkinson is also an Associate Professor of Biochemistry and Molecular and Medical Genetics at the University of Toronto.

Source:
Journal reference:

Curran, D. M., et al. (2020) Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets. eLife. doi.org/10.7554/eLife.51850.

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