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| The structure of the protein PfHAD1. Dysfunctional PfHAD1 causes the malaria parasite to be resistant to fosmidomycin.--Courtesy of Niraj H. Tolia |
Scientists at Washington University in St. Louis have discovered one method by which malaria parasites resist drugs.
The findings could help drug developers create better antibiotics against malaria and potentially other infectious diseases, including bacterial infections and tuberculosis.
In patients, researchers have observed that the investigational drug fosmidomycin blocks a process called isoprenoid synthesis in malaria, killing the parasite. Isoprenoids, molecules made in a range of organisms including the malaria parasite, play multiple roles in keeping organisms healthy. Though fosmidomycin works initially, it often becomes less effective over time--a common characteristic of current antibiotics.
In clinical trials, researchers were noticing that the malaria parasite returned in more than half the children treated with fosmidomycin.
Washington University investigators set out to uncover why this was happening. Using next-generation sequencing, the team compared the genetics of malaria parasites that responded to the drug to the genetics of those that became resistant to it. The culprit, the researchers found, was mutations in a gene called PfHAD1, which caused malaria to be resistant to fosmidomycin.
"The PfHAD1 protein is completely unstudied," said senior author Dr. Audrey Odom, assistant professor of pediatrics at Washington University, in a university news story. "It's a member of a larger family of proteins, and there are almost no biological functions assigned to them."
The findings appear July 24 in Nature Communications.
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- see the study abstract