Sleeping sickness drug resistance mechanism identified

The study highlights how the sleeping sickness parasite is affected by drugs Copyright: Flickr/ILRI

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[DOUALA, CAMEROON] UK researchers have discovered how the drugs that are currently used to treat sleeping sickness work at the molecular level, potentially opening the way to tackling growing resistance to the drugs.

Sleeping sickness (human African trypanosomiasis) is caused by Trypanosoma brucei parasites and is transmitted by the tsetse fly in Sub-Saharan Africa, where the disease affected around 30,000 people in 2011, according to the WHO.

This is a dramatic drop since 1998 when close to 300,000 people were estimated to have the disease.

But the five drugs available (suramin, pentamidine, eflornithine, melasoprol and nifurtimox) are expensive, highly toxic, require prolonged treatment periods and are increasingly becoming ineffective because of parasite resistance.  

Until recently, the scientists did not know how these drugs work or how resistance to them emerges.

"The older drugs were introduced over 60 years ago," David Horn, a researcher at the London School of Hygiene and Tropical Medicine told SciDev.Net. "They were known to kill the parasites but nothing was known about their molecular mechanism."

Now this knowledge gap has been filled.

Horn’s team used genetic screening to pinpoint exactly how the drugs enter and kill the parasite, on a cellular level, a move which may help tackle growing resistance and lead to the design of better drugs.

They found that the drugs enter the parasite via molecular ‘pumps’, and that resistance can emerge when the parasite mutates to change or remove the pumps.

"We now know what these pumps look like at the molecular level and we also know which pumps are indispensable [for the parasite’s survival]," said Horn, lead author of the study, published in Nature last month (25 January).

"This means we can develop new, durable drugs that get into the parasite cell via the indispensable pumps."

The researchers also identified 50 genes involved in the action of the drugs.

Horn hopes to use the technique to screen new drugs that are undergoing clinical trials to understand how they kill trypanosomes, and how resistance might emerge, as well as for screening veterinary drugs.

"The livestock diseases caused by African trypanosomes exert a huge economic burden in Africa and drug resistance is also a problem here," he said.

Horn now intends to team up with African researchers in endemic countries to further study drug resistance patterns.

Michael Barret, a biochemical parasitologist at the University of Glasgow, United Kingdom, said these results could speed up understanding of why resistance develops, and help make new and better drugs.

"Such drugs are desperately needed," Barret said.

Link to full paper in Nature

See below for a podcast of David Horn talking about the study:



Nature doi: 10.1038/nature10771 (2012)