A new class of compounds, which demonstrate potent antimalarial activity in preclinical studies, is reported online this week in Nature Communications. The compounds affect the malaria parasites’ ability to maintain adequate levels of sodium within their cells, leading to excessive water intake, which causes the parasites to burst.
Malaria-causing Plasmodium parasites grow within human red blood cells and are transmitted from person to person by mosquitoes. On infection, the parasite induces changes in the host cell membrane so that more nutrients are taken in, which triggers an increase in sodium concentration within red blood cells. However, the parasite keeps its own sodium levels low with the help of a protein (PfATP4), which pumps sodium out of the parasite. A class of antimalarial compounds known as spiroindolones affect this process and are currently being tested in clinical trials, however, the search for new classes is essential in the face of emerging drug resistance.
Akhil Vaidya and colleagues report that another class of compounds, called pyrazoleamides, disrupt sodium pumping and increase sodium levels in Plasmodium. This results in excessive water intake, cell swelling and eventually, bursting. The compounds are potent inhibitors of Plasmodium growth in mice with human red blood cells, leading to rapid parasite clearance when administered as a once-daily oral dose. After sustained pyrazoleamide exposure to induce resistance, fully resistant parasites appear at a very low frequency.
The results of the study confirm that targeting sodium balance in Plasmodium is a promising approach for developing new antimalarial drugs. Further research is needed to precisely identify the molecular target of the compounds and to determine whether these can be developed into effective antimalarial drugs.
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