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infecting a red blood cell
Photo courtesy of St. Jude
Children’s Research Hospital
New research helps explain how one of Plasmodium falciparum’s best weapons against antimalarial drugs can actually be exploited to treat malaria.
Investigators believe the findings, published in PLOS Pathogens, might be used to stop the emergence and spread of drug-resistant malaria.
The team noted that mutations in the P falciparum chloroquine resistance transporter (PfCRT) confer resistance to
chloroquine and related antimalarial drugs by enabling the protein to transport the drugs away from their targets within the parasite’s digestive vacuole.
However, chloroquine resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally diverse drugs. And mutations in PfCRTCQR that suppress this hypersensitivity simultaneously reinstate sensitivity to chloroquine and related drugs.
With this study, the investigators uncovered 2 mechanisms by which PfCRT causes P falciparum to become hypersensitive to antimalarial drugs.
First, they found that quinine, which normally exerts its killing effect within the parasite’s digestive vacuole, can bind tightly to certain forms of PfCRT. This blocks the function of the protein, which is essential to the parasite’s survival.
Second, the team found that amantadine, which normally sequesters within the digestive vacuole as well, is leaked back into the cytosol via PfCRT.
The investigators noted that, in both of these cases, mutations that suppress hypersensitivity also revoke PfCRT’s ability to transport chloroquine, which explains why rescue from hypersensitivity restores the parasite’s sensitivity to chloroquine.
“[C]hanges that allow the protein to move chloroquine away from its antimalarial target simultaneously enable the protein to deliver other drugs to their antimalarial targets,” explained study author Rowena Martin, PhD, of Australian National University in Canberra.
“[W]hen the protein adapts itself to fend off one of these drugs, it is no longer able to deal with chloroquine and, hence, the parasite is re-sensitized to chloroquine. Essentially, the parasite can’t have its cake and eat it too. So if chloroquine or a related drug is paired with a drug that is super-active against the modified protein, no matter what the parasite tries to do, it’s ‘checkmate’ for malaria.”
Dr Martin and her colleagues believe their findings provide a foundation for understanding and exploiting the hypersensitivity of chloroquine-resistant parasites to several antimalarial drugs that are currently available.
“Health authorities could use our research to find ways to prolong the lifespan of antimalarial drugs,” said Sashika Richards, a PhD student at Australian National University.
“The current frontline antimalarial drug, artemisinin, is already failing in Asia, and we don’t have anything to replace it. It will be at least 5 years before the next new drug makes it to market. The low-hanging fruit is gone, and it’s now very costly and time-consuming to develop new treatments for malaria.” 
infecting a red blood cell
Photo courtesy of St. Jude
Children’s Research Hospital
New research helps explain how one of Plasmodium falciparum’s best weapons against antimalarial drugs can actually be exploited to treat malaria.
Investigators believe the findings, published in PLOS Pathogens, might be used to stop the emergence and spread of drug-resistant malaria.
The team noted that mutations in the P falciparum chloroquine resistance transporter (PfCRT) confer resistance to
chloroquine and related antimalarial drugs by enabling the protein to transport the drugs away from their targets within the parasite’s digestive vacuole.
However, chloroquine resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally diverse drugs. And mutations in PfCRTCQR that suppress this hypersensitivity simultaneously reinstate sensitivity to chloroquine and related drugs.
With this study, the investigators uncovered 2 mechanisms by which PfCRT causes P falciparum to become hypersensitive to antimalarial drugs.
First, they found that quinine, which normally exerts its killing effect within the parasite’s digestive vacuole, can bind tightly to certain forms of PfCRT. This blocks the function of the protein, which is essential to the parasite’s survival.
Second, the team found that amantadine, which normally sequesters within the digestive vacuole as well, is leaked back into the cytosol via PfCRT.
The investigators noted that, in both of these cases, mutations that suppress hypersensitivity also revoke PfCRT’s ability to transport chloroquine, which explains why rescue from hypersensitivity restores the parasite’s sensitivity to chloroquine.
“[C]hanges that allow the protein to move chloroquine away from its antimalarial target simultaneously enable the protein to deliver other drugs to their antimalarial targets,” explained study author Rowena Martin, PhD, of Australian National University in Canberra.
“[W]hen the protein adapts itself to fend off one of these drugs, it is no longer able to deal with chloroquine and, hence, the parasite is re-sensitized to chloroquine. Essentially, the parasite can’t have its cake and eat it too. So if chloroquine or a related drug is paired with a drug that is super-active against the modified protein, no matter what the parasite tries to do, it’s ‘checkmate’ for malaria.”
Dr Martin and her colleagues believe their findings provide a foundation for understanding and exploiting the hypersensitivity of chloroquine-resistant parasites to several antimalarial drugs that are currently available.
“Health authorities could use our research to find ways to prolong the lifespan of antimalarial drugs,” said Sashika Richards, a PhD student at Australian National University.
“The current frontline antimalarial drug, artemisinin, is already failing in Asia, and we don’t have anything to replace it. It will be at least 5 years before the next new drug makes it to market. The low-hanging fruit is gone, and it’s now very costly and time-consuming to develop new treatments for malaria.”
infecting a red blood cell
Photo courtesy of St. Jude
Children’s Research Hospital
New research helps explain how one of Plasmodium falciparum’s best weapons against antimalarial drugs can actually be exploited to treat malaria.
Investigators believe the findings, published in PLOS Pathogens, might be used to stop the emergence and spread of drug-resistant malaria.
The team noted that mutations in the P falciparum chloroquine resistance transporter (PfCRT) confer resistance to
chloroquine and related antimalarial drugs by enabling the protein to transport the drugs away from their targets within the parasite’s digestive vacuole.
However, chloroquine resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally diverse drugs. And mutations in PfCRTCQR that suppress this hypersensitivity simultaneously reinstate sensitivity to chloroquine and related drugs.
With this study, the investigators uncovered 2 mechanisms by which PfCRT causes P falciparum to become hypersensitive to antimalarial drugs.
First, they found that quinine, which normally exerts its killing effect within the parasite’s digestive vacuole, can bind tightly to certain forms of PfCRT. This blocks the function of the protein, which is essential to the parasite’s survival.
Second, the team found that amantadine, which normally sequesters within the digestive vacuole as well, is leaked back into the cytosol via PfCRT.
The investigators noted that, in both of these cases, mutations that suppress hypersensitivity also revoke PfCRT’s ability to transport chloroquine, which explains why rescue from hypersensitivity restores the parasite’s sensitivity to chloroquine.
“[C]hanges that allow the protein to move chloroquine away from its antimalarial target simultaneously enable the protein to deliver other drugs to their antimalarial targets,” explained study author Rowena Martin, PhD, of Australian National University in Canberra.
“[W]hen the protein adapts itself to fend off one of these drugs, it is no longer able to deal with chloroquine and, hence, the parasite is re-sensitized to chloroquine. Essentially, the parasite can’t have its cake and eat it too. So if chloroquine or a related drug is paired with a drug that is super-active against the modified protein, no matter what the parasite tries to do, it’s ‘checkmate’ for malaria.”
Dr Martin and her colleagues believe their findings provide a foundation for understanding and exploiting the hypersensitivity of chloroquine-resistant parasites to several antimalarial drugs that are currently available.
“Health authorities could use our research to find ways to prolong the lifespan of antimalarial drugs,” said Sashika Richards, a PhD student at Australian National University.
“The current frontline antimalarial drug, artemisinin, is already failing in Asia, and we don’t have anything to replace it. It will be at least 5 years before the next new drug makes it to market. The low-hanging fruit is gone, and it’s now very costly and time-consuming to develop new treatments for malaria.”