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Credit: Robert Boston
Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.
The team reported this finding in Nature Communications.
The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.
Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.
But over time, the drug often becomes less effective.
“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”
Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.
This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.
“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”
Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.
Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.
“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”
Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria. 
Credit: Robert Boston
Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.
The team reported this finding in Nature Communications.
The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.
Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.
But over time, the drug often becomes less effective.
“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”
Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.
This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.
“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”
Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.
Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.
“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”
Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.
Credit: Robert Boston
Researchers have uncovered a way in which the malaria parasite Plasmodium falciparum becomes resistant to an investigational drug called fosmidomycin.
The team reported this finding in Nature Communications.
The malaria parasite makes a class of molecules called isoprenoids, which play multiple roles in keeping organisms healthy.
Fosmidomycin can be used to block isoprenoid synthesis and kill the malaria parasite.
But over time, the drug often becomes less effective.
“In trials testing fosmidomycin, the malaria parasite returned in more than half the children by the end of the study,” said Audrey R. Odom, MD, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“We wanted to know how the parasite is getting around the drug. How can it manage to live even though the drug is suppressing these compounds that are necessary for life?”
Using sequencing technology, she and her colleagues compared the genetics of malaria parasites that responded to the drug to the genetics of parasites that were resistant to it.
This revealed mutations in a gene called PfHAD1. With dysfunctional PfHAD1, malaria is resistant to fosmidomycin.
“The PfHAD1 protein is completely unstudied,” Dr Odom said. “It’s a member of a larger family of proteins, and there are almost no biological functions assigned to them.”
Dr Odom’s team showed that, in malaria parasites, the PfHAD1 protein normally slows down the synthesis of isoprenoids. In other words, when present, PfHAD1 is doing the same job as the drug, slowing isoprenoid manufacturing.
Since isoprenoids are necessary for life, it’s not clear why the organism would purposefully slow down isoprenoid production.
“We don’t know why the protein puts the brakes on under normal conditions; perhaps simply because it’s an energetically expensive pathway,” Dr Odom said. “But loss of PfHAD1 releases the brakes, increasing the pathway’s activity, so that even when the drug is there, it doesn’t kill the cells.”
Therefore, Dr Odom and her colleagues believe isoprenoid synthesis is an attractive drug target for malaria.