Drug resistance may make malaria parasites vulnerable to other substances
Researchers say their discovery could reveal potential new drug options
Malaria parasites that develop resistance to the most effective class of anti-malarial drugs may become susceptible to other treatments as a result, researchers at St George’s, University of London, UK have revealed in a study. The discovery could reveal potential new drug options, which would be essential in the event of resistance to the best anti-malarials.
The researchers have shown how the anti-malarials artemisinins attack the malaria parasite by inhibiting the action of a crucial protein, and that genetic mutations in this protein can reduce the effect of the drugs.
While demonstrating this, they also discovered that a mutation that gives the parasite resistance to artemisinins makes it more sensitive to attack by another substance, cyclopiazonic acid (CPA). CPA is thought to be too toxic to be a suitable anti-malarial treatment, but the findings suggest it could be worth pursuing derivatives of the acid as treatment options.
The research has been published in The Journal of Infectious Diseases.
The yeast model provides a convenient and reliable method to study anti-malarials and this particular mechanism of resistance to them
The artemisinin group of drugs are the most effective and widely used treatments for malaria – used most powerfully with other drugs as artemisinin-based combination therapies – but little is known about their mechanism of action on the malaria parasite. There are signs that the parasite is developing resistance to such therapies, meaning that further understanding of the drugs could be crucial to prevent them from becoming obsolete.
The researchers demonstrated that artemisinins work by acting on a protein within the parasite called a calcium pump, which regulates calcium levels in cells, and if it is not functioning properly the parasite dies.
In previous studies, the team saw the same effect on the calcium pump in genetically engineered malaria parasites. However, in these studies the parasites’ sensitivity to artemisinins fluctuated, so they did not give a clear indication of the drugs’ mechanism of action and the findings could not be confirmed.
To provide more consistent results, the latest study used yeast cells instead of parasite cells.
After confirming that artemisinins inhibited the calcium pump in the yeast model, the researchers mutated the pump to mimic three mutations previously observed to give parasites resistance to the drugs. When they did this, they saw similar resistance.
The latest study used yeast cells instead of parasite cells
Following this, they tested whether these mutations had any effect on the action of another five substances known to have an anti-malarial effect. They found that one particular mutation that gave the pump resistance to artemisinins made it more susceptible to CPA.
Their findings also showed that the yeast model could be used to identify other drugs that harm the parasite.
Lead author Professor Sanjeev Krishna said: ‘CPA is a compound used in science and not in clinical practice in any way. However, it points to a proof of concept that we can look for weaknesses in the more resistant strains of the parasite. The yeast model provides a convenient and reliable method to study anti-malarials and this particular mechanism of resistance to them.’
