AsianScientist (Apr. 19, 2016) – Researchers in Singapore have developed a dual-acting malaria drug that kills off drug-resistant mosquitoes by effectively trapping chloroquine in their ‘stomachs.’ Their work was published in Antimicrobial Agents and Chemotherapy.
This hybrid drug, that combines parts of chloroquine and a chemoreversal agent, was developed by Associate Professor Kevin Tan and Associate Professor Brian Dymock from the National University of Singapore. The chemoreversal agent acts on a faulty ‘window’ of the parasite’s stomach so that it can close, while chloroquine becomes so concentrated inside the stomach of the drug-resistant parasite that it eventually dies off.
Artemisinin combination therapy (ACT) is currently the best malaria treatment, as recommended by the World Health Organization. However, in early 2015, artemisinin-resistant malaria was confirmed in five countries in Southeast Asia: Cambodia, Laos, Myanmar, Thailand and Vietnam.
Even more worryingly, malaria cases that are resistant to practically all drugs have begun to emerge along the Thailand-Cambodia border. Such cases do not respond to ACT; thus, new therapies that are effective for resistant malaria are urgently needed.
For a therapy to be effective, it needs to counteract the resistance of malaria to existing drugs. Malaria drugs, such as chloroquine and artemisinin, work within the digestive vacuole of the malaria parasite, which serves as its ‘stomach.’
However, in a resistant malaria parasite, the stomach membrane is mutated so that it cannot keep the drug inside the stomach, much like a window with a broken lock. With this hybrid drug, once chloroquine enters the parasite’s stomach, the stomach membrane traps the drug within—similar to a window closing and locking—and the high levels of drug can then effectively kill the parasite.
The drug killed malaria strains grown in the laboratory, as well as malaria parasites from patients in Thailand. Importantly, the drug was very effective against malaria that was resistant to both chloroquine and artemisinin. In fact, it was three times more effective than chloroquine at killing these resistant strains.
Although malaria drugs and chemoreversal agents have been used to treat drug-resistant malaria before, this is the first time that a hybrid of chloroquine and a newly-discovered chemoreversal factor has been used in a single novel molecule for this purpose.
Furthermore, a single therapy has several advantages that make it a promising new weapon against drug-resistant malaria. Besides being more convenient to take, it has less risk of drug-drug interactions; may be better absorbed and distributed in the body; and could result in slower development of new resistant strains of malaria.
The researchers are continuing to refine the hybrid drug to make it an even more effective therapy for resistant malaria.
The article can be found at: Boudhar et al. (2016) Overcoming Chloroquine Resistance in Malaria: Design, Synthesis and Structure-Activity Relationships of Novel Hybrid Compounds.
Source: National University of Singapore; Photo: Shutterstock.
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