Grant: Project Grant

Soil-transmitted helminths (STHs) like hookworms infect over a billion people causing malnutrition and death, with the greatest effects on children. Drugs for treating STH infections exist but there are few such drugs and resistance to these is growing. It is urgent that we develop new drugs to treat these major human infections. Our goal here is to find such new drugs. The key is to find a drug that kills the STH while leaving the human host untouched and we exploit the differences between host and parasite to do this. One key difference between humans and STHs is how they make energy. Humans breathe oxygen and this is how we burn our food to make energy. STHs often live in the human gut - there is little oxygen and they adapted to use an unusual way to make energy. This relies on a small molecule called rhodoquinone (RQ) - without it they cannot survive. The beauty of RQ is that it is only made by the parasites - if we could stop the parasite making RQ, we could kill the worm without affecting its host. RQ is a perfect target. We showed the nematode worm C.elegans makes RQ and unpicked how it makes RQ and the genes involved. We set up a simple way to test for new drugs that block RQ synthesis and screened ~50,000 compounds in these tests. Excitingly, we found several new classes of possible drugs and showed that some are very powerful at killing parasites when they use RQ, suggesting our approach works. We now want to scale this up to screen 100,000 compounds for new blockers and confirm these by testing directly on parasites. We also found some key parasite proteins are subtly changed so they are different to their host counterparts. We used computers to predict drugs that may block the STH and not the host protein and we will test these drugs in C.elegans. By combining large screens of compounds in C.elegans and predictions in computers we will find new drugs that kill parasites by blocking key steps in their metabolism.