Genetic mutation in African malaria parasite shown to give resistance to best drugs

The artemisinin group of drugs are the most effective and widely used treatments for malaria. They are most powerful and less likely to be resisted by the malaria parasite when used with other drugs as artemisinin-based combination therapies (ACTs). But the new study confirms previous suggestions that mutations in a key part of the parasite can provide resistance to artemether, one of the two most effective artemisinins.

The research group, led by a team at St George's, University of London, discovered artemether resistance in parasite samples taken from 11 of the 28 malaria-infected patients in the study. On average, artemether's effectiveness was reduced by half. Each parasite was found to have the same genetic mutations.

The patients were infected by malaria parasite-carrying mosquitoes while travelling abroad, mostly in sub-Saharan Africa, home to 90 per cent of the one million people killed worldwide each year by malaria.

Study lead Professor Sanjeev Krishna said: "Artemether and ACTs are still very effective, but this study confirms our fears of how the parasite is mutating to develop resistance. Drug resistance could eventually become a devastating problem in Africa, and not just in south east Asia where most of the world is watching for resistance. Effective alternative treatments are currently unaffordable for most suffering from malaria. Finding new drugs is, therefore, crucial."

In the study, published online April 27, 2012 in BioMed Central's open access journal Malaria Journal, the researchers tested samples from patients infected with the Plasmodium falciparum parasite. This parasite causes the deadliest form of malaria, and is responsible for nine out of 10 malaria deaths. The parasites were assessed for their sensitivity to four artemisinins -- artemisinin itself, artemether, dihydroartemisinin and artesunate.

The 11 parasites showing artemether resistance had the same genetic mutations in an internal system called the calcium pump. This is used to transport calcium, crucial for the parasite to function. The researchers already suspected that the calcium pump -- which they first showed was a target for artemisinins to work on in 2003 -- had the potential to develop artemisinin resistance. But this had been difficult to confirm until now.

Artemether resistance was strongest in several cases where a separate mutation in another transport system -- a protein called pfmdr1, already associated with drug resistance -- also occurred.

The effectiveness of the other artemisinins was not significantly affected by the mutations. This may be because they were able to work on other transport systems in the parasite, compensating for the effects of resistance mutations in the calcium pump.

However, Professor Krishna added: "At the moment, we do not know if the other artemisinins will follow suit, but given the shared chemistry they have with artemether it is tempting to think that they would."

He added that resistance could be a result of the increasing use of ACTs, 300 million doses of which were dispensed worldwide in 2011. Greater use could offer the parasites more opportunities to develop genetic mutations that provide resistance. This could, the researchers say, lead to a repeat of how the parasite developed resistance to pre-artemisinin drugs such as chloroquine. Incorrect use of anti-malarials, such as not completing the treatment course or taking sub-standard drugs, could aid this process.

Professor Krishna said: "New drug development is paramount, but it is vital that we also learn more about how artemisinins work so we can tailor ACT treatments to be effective for as long as possible."