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Credit: Ute Frevert
and Margaret Shear
Changing the administration of chloroquine might prevent resistance to the antimalarial agent, according to a study published in PNAS.
Investigators found the parasite protein that causes chloroquine resistance—the Plasmodium falciparum chloroquine resistance transporter (PfCRT)—has an Achilles’ heel.
“We studied diverse versions of this protein and, in all cases, found that it is limited in its capacity to remove the drug from the parasite,” said Rowena Martin, PhD, of The Australian National University in Canberra.
“This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day.”
Dr Martin and her colleagues noted that a number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to chloroquine resistance.
So they set out to characterize these forms of PfCRT and determine the number of mutations, as well as the order of their addition, required to confer chloroquine transport activity.
The investigators analyzed more than 100 variants of PfCRT, measuring their ability to transport chloroquine.
The team identified multiple mutational pathways that led to chloroquine transport via PfCRT but divided these pathways into 2 main lineages.
“We found that the protein gains the ability to move chloroquine out of the parasite through 1 of 2 evolutionary pathways but that this process is rigid,” Dr Martin said. “One wrong turn, and the protein is rendered useless.”
In fact, the investigators found that, if mutations did not occur in a precise order, chloroquine transport activity decreased.
The number of mutations played a key role as well. A minimum of 2 mutations was sufficient for chloroquine transport activity, but as few as 4 conferred full activity.
“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies,” Dr Martin said.
She also noted that these findings might not apply only to chloroquine. They might apply to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance. 
Credit: Ute Frevert
and Margaret Shear
Changing the administration of chloroquine might prevent resistance to the antimalarial agent, according to a study published in PNAS.
Investigators found the parasite protein that causes chloroquine resistance—the Plasmodium falciparum chloroquine resistance transporter (PfCRT)—has an Achilles’ heel.
“We studied diverse versions of this protein and, in all cases, found that it is limited in its capacity to remove the drug from the parasite,” said Rowena Martin, PhD, of The Australian National University in Canberra.
“This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day.”
Dr Martin and her colleagues noted that a number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to chloroquine resistance.
So they set out to characterize these forms of PfCRT and determine the number of mutations, as well as the order of their addition, required to confer chloroquine transport activity.
The investigators analyzed more than 100 variants of PfCRT, measuring their ability to transport chloroquine.
The team identified multiple mutational pathways that led to chloroquine transport via PfCRT but divided these pathways into 2 main lineages.
“We found that the protein gains the ability to move chloroquine out of the parasite through 1 of 2 evolutionary pathways but that this process is rigid,” Dr Martin said. “One wrong turn, and the protein is rendered useless.”
In fact, the investigators found that, if mutations did not occur in a precise order, chloroquine transport activity decreased.
The number of mutations played a key role as well. A minimum of 2 mutations was sufficient for chloroquine transport activity, but as few as 4 conferred full activity.
“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies,” Dr Martin said.
She also noted that these findings might not apply only to chloroquine. They might apply to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance.
Credit: Ute Frevert
and Margaret Shear
Changing the administration of chloroquine might prevent resistance to the antimalarial agent, according to a study published in PNAS.
Investigators found the parasite protein that causes chloroquine resistance—the Plasmodium falciparum chloroquine resistance transporter (PfCRT)—has an Achilles’ heel.
“We studied diverse versions of this protein and, in all cases, found that it is limited in its capacity to remove the drug from the parasite,” said Rowena Martin, PhD, of The Australian National University in Canberra.
“This means malaria could once again be treated with chloroquine if it is administered twice-daily, rather than just once a day.”
Dr Martin and her colleagues noted that a number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to chloroquine resistance.
So they set out to characterize these forms of PfCRT and determine the number of mutations, as well as the order of their addition, required to confer chloroquine transport activity.
The investigators analyzed more than 100 variants of PfCRT, measuring their ability to transport chloroquine.
The team identified multiple mutational pathways that led to chloroquine transport via PfCRT but divided these pathways into 2 main lineages.
“We found that the protein gains the ability to move chloroquine out of the parasite through 1 of 2 evolutionary pathways but that this process is rigid,” Dr Martin said. “One wrong turn, and the protein is rendered useless.”
In fact, the investigators found that, if mutations did not occur in a precise order, chloroquine transport activity decreased.
The number of mutations played a key role as well. A minimum of 2 mutations was sufficient for chloroquine transport activity, but as few as 4 conferred full activity.
“This indicates that the protein is under conflicting pressures, which is a weakness that could be exploited in future antimalarial strategies,” Dr Martin said.
She also noted that these findings might not apply only to chloroquine. They might apply to several chloroquine-like drugs that are also becoming less effective as the malaria parasite builds up resistance.